Human secreted proteins

ABSTRACT

The present invention relates to human secreted polypeptides, and isolated nucleic acid molecules encoding said polypeptides, useful for diagnosing and treating cardiovascular diseases, disorders, and/or conditions related thereto. Antibodies that bind these polypeptides are also encompassed by the present invention. Also encompassed by the invention are vectors, host cells and recombinant and synthetic methods for producing said polynucleotides, polypeptides, and/or antibodies. The invention further encompasses screening methods for identifying agonists and antagonists of polynucleotides and polypeptides of the invention. The present invention further encompasses methods and compositions for inhibiting or enhancing the production and function of the polypeptides of the present invention.

FIELD OF THE INVENTION

The present invention relates to human secreted proteins/polypeptides,and isolated nucleic acid molecules encoding said proteins/polypeptides,useful for detecting, preventing, diagnosing, prognosticating, treating,and/or ameliorating cardiovascular diseases, disorders, and/orconditions related thereto. Antibodies that bind these polypeptides arealso encompassed by the present invention. Also encompassed by theinvention are vectors, host cells, and recombinant and synthetic methodsfor producing said polynucleotides, polypeptides, and/or antibodies. Theinvention further encompasses screening methods for identifying agonistsand antagonists of polynucleotides and polypeptides of the invention.The present invention further encompasses methods and compositions forinhibiting or enhancing the production and function of the polypeptidesof the present invention.

BACKGROUND OF THE INVENTION

The cardiovascular system is a component of a complex physiologicalnetwork involved in maintaining the oxygen and nutrient supply totissues of the body.

The heart is the anatomical and functional centerpiece of thecardiovascular system. Weighing only 250-350 grams (less than a pound),the heart is one of our strongest and hardest working organs. It iscomposed of innervated muscle tissue with unique properties; e.g., itcan pace itself in contraction. The main center of rhythm regulation isthe sinoatrial (SA) node. Certain cardiac cells repeatedly fire impulsesthat trigger heart contractions. These autorhythmic cells have twoimportant functions. One is to act as a pacemaker (set the pace for theentire heart), and the other is to form a conduction system, the routefor conducting impulses throughout the heart muscle. This conductionsystem controls the pattern of blood flow through the heart.

The heart pumps at least five quarts of blood through a full circuit ofthe body every minute. The heart consists of two pumps, side by side.The pump on the right side moves blood to the lungs, where waste gases,such as carbon dioxide, are removed and oxygen is added. Freshlyoxygenated blood returns to the pump on the left side, which moves itout into the rest of the body.

Blood flows away from the heart to the lungs or to the rest of yourbody, though blood vessels called arteries. Arteries branch extensively,each branch become smaller, forming blood vessels called arterioles.Arterioles also become repeatedly smaller and smaller until they aretiny vessels called capillaries. Throughout the arteries and smallervessels that stem from them, the blood delivers nutrients and oxygen tothe tissues and picks up waste. This task is completed in thecapillaries. As the blood moves on through the capillaries the bloodvessels gradually become larger, eventually becoming veins. Veinsultimately carry blood back to the heart. The cycle then begins again.

Disorders of the cardiovascular system are many and varied, killing moreAmericans each year than any other category of disorders. For example,damage to the conduction system leads to arrhythmia, an irregularbeating of the heart. If left untreated, the heart becomes unable toeffectively pump blood, frequently leading to permanent heart damageand/or cardiac arrest.

One of the most prevalent conditions in industrialized countries todayis atherosclerosis. Atherosclerosis is the buildup of fatty deposits inthe intima of large and medium-sized arteries. The buildup of depositsnarrowing of the arteries, reducing or potentially blocking the abilityof blood to flow through the arteries. Untreated, atherosclerosistypically results in cardiac arrest and, frequently, death.

Clearly, the discovery of new human cardiovascular-associatedpolynucleotides, the polypeptides encoded by them, and antibodies thatimmunospecifically bind these polypeptides, satisfies a need in the artby providing new compositions which are useful in the diagnosis,treatment, prevention and/or prognosis of cardiovascular disorders.

Cardiovascular disorders include, but are not limited to, stroke,cardiovascular abnormalities, such as arterio-arterial fistula,arteriovenous fistula, cerebral arteriovenous malformations, congenitalheart defects, pulmonary atresia, and Scimitar Syndrome. Congenitalheart defects include, but are not limited to, aortic coarctation, cortriatriatum, coronary vessel anomalies, crisscross heart, dextrocardia,patent ductus arteriosus, Ebstein's anomaly, Eisenmenger complex,hypoplastic left heart syndrome, levocardia, tetralogy of fallot,transposition of great vessels, double outlet right ventricle, tricuspidatresia, persistent truncus arteriosus, and heart septal defects, suchas aortopulmonary septal defect, endocardial cushion defects,Lutembacher's Syndrome, trilogy of Fallot, ventricular heart septaldefects.

Cardiovascular disorders also include, but are not limited to, heartdisease, such as arrhythmias, carcinoid heart disease, high cardiacoutput, low cardiac output, cardiac tamponade, endocarditis (includingbacterial), heart aneurysm, cardiac arrest, congestive heart failure,congestive cardiomyopathy, paroxysmal dyspnea, cardiac edema, hearthypertrophy, congestive cardiomyopathy, left ventricular hypertrophy,right ventricular hypertrophy, post-infarction heart rupture,ventricular septal rupture, heart valve diseases, myocardial diseases,myocardial ischemia, pericardial effusion, pericarditis (includingconstrictive and tuberculous), pneumopericardium, postpericardiotomysyndrome, pulmonary heart disease, rheumatic heart disease, ventriculardysfunction, hyperemia, cardiovascular pregnancy complications, ScimitarSyndrome, cardiovascular syphilis, and cardiovascular tuberculosis.

Arrhythmias include, but are not limited to, sinus arrhythmia, atrialfibrillation, atrial flutter, bradycardia, extrasystole, Adams-StokesSyndrome, bundle-branch block, sinoatrial block, long QT syndrome,parasystole, Lown-Ganong-Levine Syndrome, Mahaim-type pre-excitationsyndrome, Wolff-Parkinson-White syndrome, sick sinus syndrome,tachycardias, and ventricular fibrillation. Tachycardias includeparoxysmal tachycardia, supraventricular tachycardia, acceleratedidioventricular rhythm, atrioventricular nodal reentry tachycardia,ectopic atrial tachycardia, ectopic junctional tachycardia, sinoatrialnodal reentry tachycardia, sinus tachycardia, Torsades de Pointes, andventricular tachycardia.

Heart valve diseases include, but are not limited to, aortic valveinsufficiency, aortic valve stenosis, hear murmurs, aortic valveprolapse, mitral valve prolapse, tricuspid valve prolapse, mitral valveinsufficiency, mitral valve stenosis, pulmonary atresia, pulmonary valveinsufficiency, pulmonary valve stenosis, tricuspid atresia, tricuspidvalve insufficiency, and tricuspid valve stenosis.

Myocardial diseases include, but are not limited to, alcoholiccardiomyopathy, congestive cardiomyopathy, hypertrophic cardiomyopathy,aortic subvalvular stenosis, pulmonary subvalvular stenosis, restrictivecardiomyopathy, Chagas cardiomyopathy, endocardial fibroelastosis,endomyocardial fibrosis, Keams Syndrome, myocardial reperfusion injury,and myocarditis.

Myocardial ischemias include, but are not limited to, coronary disease,such as angina pectoris, coronary aneurysm, coronary arteriosclerosis,coronary thrombosis, coronary vasospasm, myocardial infarction andmyocardial stunning.

Cardiovascular diseases also include vascular diseases such asaneurysms, angiodysplasia, angiomatosis, bacillary angiomatosis,Hippel-Lindau Disease, Klippel-Trenaunay-Weber Syndrome, Sturge-WeberSyndrome, angioneurotic edema, aortic diseases, Takayasu's Arteritis,aortitis, Leriche's Syndrome, arterial occlusive diseases, arteritis,enarteritis, polyarteritis nodosa, cerebrovascular disorders, diabeticangiopathies, diabetic retinopathy, embolisms, thrombosis,erythromelalgia, hemorrhoids, hepatic veno-occlusive disease,hypertension, hypotension, ischemia, peripheral vascular diseases,phlebitis, pulmonary veno-occlusive disease, Raynaud's disease, CRESTsyndrome, retinal vein occlusion, Scimitar syndrome, superior vena cavasyndrome, telangiectasia, atacia telangiectasia, hereditary hemorrhagictelangiectasia, varicocele, varicose veins, varicose ulcer, vasculitis,and venous insufficiency.

Aneurysms include, but are not limited to, dissecting aneurysms, falseaneurysms, infected aneurysms, ruptured aneurysms, aortic aneurysms,cerebral aneurysms, coronary aneurysms, heart aneurysms, and iliacaneurysms.

Arterial occlusive diseases include, but are not limited to,arteriosclerosis, intermittent claudication, carotid stenosis,fibromuscular dysplasias, mesenteric vascular occlusion, Moyamoyadisease, renal artery obstruction, retinal artery occlusion, andthromboangiitis obliterans.

Cerebrovascular disorders include, but are not limited to, carotidartery diseases, cerebral amyloid angiopathy, cerebral aneurysm,cerebral anoxia, cerebral arteriosclerosis, cerebral arteriovenousmalformation, cerebral artery diseases, cerebral embolism andthrombosis, carotid artery thrombosis, sinus thrombosis, Wallenberg'ssyndrome, cerebral hemorrhage, epidural hematoma, subdural hematoma,subaraxhnoid hemorrhage, cerebral infarction, cerebral ischemia(including transient), subclavian steal syndrome, periventricularleukomalacia, vascular headache, cluster headache, migraine, andvertebrobasilar insufficiency.

Embolisms include, but are not limited to, air embolisms, amniotic fluidembolisms, cholesterol embolisms, blue toe syndrome, fat embolisms,pulmonary embolisms, and thromoboembolisms. Thrombosis include, but arenot limited to, coronary thrombosis, hepatic vein thrombosis, retinalvein occlusion, carotid artery thrombosis, sinus thrombosis,Wallenberg's syndrome, and thrombophlebitis.

Ischemic disorders include, but are not limited to, cerebral ischemia,ischemic colitis, compartment syndromes, anterior compartment syndrome,myocardial ischemia, reperfusion injuries, and peripheral limb ischemia.Vasculitis includes, but is not limited to, aortitis, arteritis,Behcet's Syndrome, Churg-Strauss Syndrome, mucocutaneous lymph nodesyndrome, thromboangiitis obliterans, hypersensitivity vasculitis,Schoenlein-Henoch purpura, allergic cutaneous vasculitis, and Wegener'sgranulomatosis.

SUMMARY OF THE INVENTION

The present invention encompasses human secreted proteins/polypeptides;and isolated nucleic acid molecules encoding said proteins/polypeptides,useful for detecting, preventing, diagnosing, prognosticating, treating,and/or ameliorating cardiovascular diseases and disorders. Antibodiesthat bind these polypeptides are also encompassed by the presentinvention; as are vectors, host cells, and recombinant and syntheticmethods for producing said polynucleotides, polypeptides, and/orantibodies. The invention further encompasses screening methods foridentifying agonists and antagonists of polynucleotides and polypeptidesof the invention. The present invention also encompasses methods andcompositions for inhibiting or enhancing the production and function ofthe polypeptides of the present invention.

DETAILED DESCRIPTION

Polynucleotides and Polypeptides of the Invention

Description of Table 1A

Table 1A summarizes information concerning certain polynucleotides andpolypeptides of the invention. The first column provides the gene numberin the application for each clone identifier. The second column providesa unique clone identifier, “Clone ID:”, for a cDNA clone related to eachcontig sequence disclosed in Table 1A. Third column, the cDNA Clonesidentified in the second column were deposited as indicated in the thirdcolumn (i.e. by ATCC Deposit No:Z and deposit date). Some of thedeposits contain multiple different clones corresponding to the samegene. In the fourth column, “Vector” refers to the type of vectorcontained in the corresponding cDNA Clone identified in the secondcolumn. In the fifth column, the nucleotide sequence identified as “NTSEQ ID NO:X” was assembled from partially homologous (“overlapping”)sequences obtained from the corresponding cDNA clone identified in thesecond column and, in some cases, from additional related cDNA clones.The overlapping sequences were assembled into a single contiguoussequence of high redundancy (usually three to five overlapping sequencesat each nucleotide position), resulting in a final sequence identifiedas SEQ ID NO:X. In the sixth column, “Total NT Seq.” refers to the totalnumber of nucleotides in the contig sequence identified as SEQ ID NO:X.”The deposited clone may contain all or most of these sequences,reflected by the nucleotide position indicated as “5′ NT of Clone Seq.”(seventh column) and the “3′ NT of Clone Seq.” (eighth column) of SEQ IDNO:X. In the ninth column, the nucleotide position of SEQ ID NO:X of theputative start codon (methionine) is identified as “5′ NT of StartCodon.” Similarly, in column ten, the nucleotide position of SEQ ID NO:Xof the predicted signal sequence is identified as “5′ NT of First AA ofSignal Pep.” In the eleventh column, the translated amino acid sequence,beginning with the methionine, is identified as “AA SEQ ID NO:Y,”although other reading frames can also be routinely translated usingknown molecular biology techniques. The polypeptides produced by thesealternative open reading frames are specifically contemplated by thepresent invention.

In the twelfth and thirteenth columns of Table 1A, the first and lastamino acid position of SEQ ID NO:Y of the predicted signal peptide isidentified as “First AA of Sig Pep” and “Last AA of Sig Pep.” In thefourteenth column, the predicted first amino acid position of SEQ IDNO:Y of the secreted portion is identified as “Predicted First AA ofSecreted Portion”. The amino acid position of SEQ ID NO:Y of the lastamino acid encoded by the open reading frame is identified in thefifteenth column as “Last AA of ORF”.

SEQ ID NO:X (where X may be any of the polynucleotide sequencesdisclosed in the sequence listing) and the translated SEQ ID NO:Y (whereY may be any of the polypeptide sequences disclosed in the sequencelisting) are sufficiently accurate and otherwise suitable for a varietyof uses well known in the art and described further below. For instance,SEQ ID NO:X is useful for designing nucleic acid hybridization probesthat will detect nucleic acid sequences contained in SEQ ID NO:X or thecDNA contained in the deposited clone. These probes will also hybridizeto nucleic acid molecules in biological samples, thereby enabling avariety of forensic and diagnostic methods of the invention. Similarly,polypeptides identified from SEQ ID NO:Y may be used, for example, togenerate antibodies which bind specifically to proteins containing thepolypeptides and the secreted proteins encoded by the cDNA clonesidentified in Table 1A and/or elsewhere herein

Nevertheless, DNA sequences generated by sequencing reactions cancontain sequencing errors. The errors exist as misidentifiednucleotides, or as insertions or deletions of nucleotides in thegenerated DNA sequence. The erroneously inserted or deleted nucleotidescause frame shifts in the reading frames of the predicted amino acidsequence. In these cases, the predicted amino acid sequence divergesfrom the actual amino acid sequence, even though the generated DNAsequence may be greater than 99.9% identical to the actual DNA sequence(for example, one base insertion or deletion in an open reading frame ofover 1000 bases).

Accordingly, for those applications requiring precision in thenucleotide sequence or the amino acid sequence, the present inventionprovides not only the generated nucleotide sequence identified as SEQ IDNO:X, and the predicted translated amino acid sequence identified as SEQID NO:Y, but also a sample of plasmid DNA containing a human cDNA of theinvention deposited with the ATCC, as set forth in Table 1A. Thenucleotide sequence of each deposited plasmid can readily be determinedby sequencing the deposited plasmid in accordance with known methods

The predicted amino acid sequence can then be verified from suchdeposits. Moreover, the amino acid sequence of the protein encoded by aparticular plasmid can also be directly determined by peptide sequencingor by expressing the protein in a suitable host cell containing thedeposited human cDNA, collecting the protein, and determining itssequence.

Also provided in Table 1A is the name of the vector which contains thecDNA plasmid. Each vector is routinely used in the art. The followingadditional information is provided for convenience.

Vectors Lambda Zap (U.S. Pat. Nos. 5,128,256 and 5,286,636), Uni-Zap XR(U.S. Pat. Nos. 5,128,256 and 5,286,636), Zap Express (U.S. Pat. Nos.5,128,256 and 5,286,636), pBluescript (pBS) (Short, J. M. et al.,Nucleic Acids Res. 16:7583-7600 (1988); Alting-Mees, M. A. and Short, J.M., Nucleic Acids Res. 17:9494 (1989)) and pBK (Alting-Mees, M. A. etal., Strategies 5:58-61 (1992)) are commercially available fromStratagene Cloning Systems, Inc., 11011 N. Torrey Pines Road, La Jolla,Calif., 92037. pBS contains an ampicillin resistance gene and pBKcontains a neomycin resistance gene. Phagemid pBS may be excised fromthe Lambda Zap and Uni-Zap XR vectors, and phagemid pBK may be excisedfrom the Zap Express vector. Both phagemids may be transformed into E.coli strain XL-1 Blue, also available from Stratagene

Vectors pSport1, pCMVSport 1.0, pCMVSport 2.0 and pCMVSport 3.0, wereobtained from Life Technologies, Inc., P.O. Box 6009, Gaithersburg, Md.20897. All Sport vectors contain an ampicillin resistance gene and maybe transformed into E. coli strain DH10B, also available from LifeTechnologies. See, for instance, Gruber, C. E., et al., Focus 15:59(1993). Vector lafmid BA (Bento Soares, Columbia University, New York,N.Y.) contains an ampicillin resistance gene and can be transformed intoE. coli strain XL-1 Blue. Vector pCR@2.1, which is available fromInvitrogen, 1600 Faraday Avenue, Carlsbad, Calif. 92008, contains anampicillin resistance gene and may be transformed into E. coli strainDH10B, available from Life Technologies. See, for instance, Clark, J.M., Nuc. Acids Res. 16:9677-9686 (1988) and Mead, D. et al.,Bio/Technology 9: (1991).

The present invention also relates to the genes corresponding to SEQ IDNO:X, SEQ ID NO:Y, and/or a deposited cDNA (cDNA Clone ID). Thecorresponding gene can be isolated in accordance with known methodsusing the sequence information disclosed herein. Such methods include,but are not limited to, preparing probes or primers from the disclosedsequence and identifying or amplifying the corresponding gene fromappropriate sources of genomic material.

Also provided in the present invention are allelic variants, orthologs,and/or species homologs. Procedures known in the art can be used toobtain full-length genes, allelic variants, splice variants, full-lengthcoding portions, orthologs, and/or species homologs of genescorresponding to SEQ ID NO:X and SEQ ID NO:Y using information from thesequences disclosed herein or the clones deposited with the ATCC. Forexample, allelic variants and/or species homologs may be isolated andidentified by making suitable probes or primers from the sequencesprovided herein and screening a suitable nucleic acid source for allelicvariants and/or the desired homologue.

The present invention provides a polynucleotide comprising, oralternatively consisting of, the nucleic acid sequence of SEQ ID NO:Xand/or a cDNA contained in ATCC Deposit No.Z. The present invention alsoprovides a polypeptide comprising, or alternatively, consisting of, thepolypeptide sequence of SEQ ID NO:Y, a polypeptide encoded by SEQ IDNO:X, and/or a polypeptide encoded by a cDNA contained in ATCC depositNo.Z. Polynucleotides encoding a polypeptide comprising, oralternatively consisting of the polypeptide sequence of SEQ ID NO:Y, apolypeptide encoded by SEQ ID NO:X and/or a polypeptide encoded by thecDNA contained in ATCC Deposit No.Z, are also encompassed by theinvention. The present invention further encompasses a polynucleotidecomprising, or alternatively consisting of the complement of the nucleicacid sequence of SEQ ID NO:X, and/or the complement of the coding strandof the cDNA contained in ATCC Deposit No.Z.

Description of Table 1B (Comprised of Tables 1B.1 and 1B.2)

Table 1B.1 and Table 1B.2 summarize some of the polynucleotidesencompassed by the invention (including cDNA clones related to thesequences (Clone ID:), contig sequences (contig identifier (Contig ID:)and contig nucleotide sequence identifiers (SEQ ID NO:X)) and furthersummarizes certain characteristics of these polynucleotides and thepolypeptides encoded thereby. The first column of Tables 1B.1 and 1B.2provide the gene numbers in the application for each clone identifier.The second column of Tables 1B.1 and 1B.2 provide unique cloneidentifiers, “Clone ID:”, for cDNA clones related to each contigsequence disclosed in Table 1A and/or Table 1B. The third column ofTables 1B.1 and 1B.2 provide unique contig identifiers, “Contig ID:” foreach of the contig sequences disclosed in these tables. The fourthcolumn of Tables 1B.1 and 1B.2 provide the sequence identifiers, “SEQ IDNO:X”, for each of the contig sequences disclosed in Table 1A and/or 1B.

Table 1B.1

The fifth column of Table 1B.1, “ORF (From-To)”, provides the location(i.e., nucleotide position numbers) within the polynucleotide sequenceof SEQ ID NO:X that delineates the preferred open reading frame (ORF)that encodes the amino acid sequence shown in the sequence listing andreferenced in Table 1B.1 as SEQ ID NO:Y (column 6). Column 7 of Table1B.1 lists residues comprising predicted epitopes contained in thepolypeptides encoded by each of the preferred ORFs (SEQ ID NO:Y).Identification of potential immunogenic regions was performed accordingto the method of Jameson and Wolf (CABIOS, 4; 181-186 (1988));specifically, the Genetics Computer Group (GCG) implementation of thisalgorithm, embodied in the program PEPTIDESTRUCTURE (Wisconsin Packagev10.0, Genetics Computer Group (GCG), Madison, Wis.). This methodreturns a measure of the probability that a given residue is found onthe surface of the protein. Regions where the antigenic index score isgreater than 0.9 over at least 6 amino acids are indicated in Table 1B.1as “Predicted Epitopes”. In particular embodiments, polypeptides of theinvention comprise, or alternatively consist of, one, two, three, four,five or more of the predicted epitopes described in Table 1B.1. It willbe appreciated that depending on the analytical criteria used to predictantigenic determinants, the exact address of the determinant may varyslightly. Column 8 of Table 1B.1 (“Cytologic Band”) provides thechromosomal location of polynucleotides corresponding to SEQ ID NO:X.Chromosomal location was determined by finding exact matches to EST andcDNA sequences contained in the NCBI (National Center for BiotechnologyInformation) UniGene database. Given a presumptive chromosomal location,disease locus association was determined by comparison with the MorbidMap, derived from Online Mendelian Inheritance in Man (Online MendelianInheritance in Man, OMIM™. McKusick-Nathans Institute for GeneticMedicine, Johns Hopkins University (Baltimore, Md.) and National Centerfor Biotechnology Information, National Library of Medicine (Bethesda,Md.) 2000. World Wide Web URL: http://www.ncbi.nlm.nih.gov/omim/). Ifthe putative chromosomal location of the Query overlaps with thechromosomal location of a Morbid Map entry, an OMIM identificationnumber is disclosed in Table 1B.1, column 9 labeled “OMIM DiseaseReference(s)”. A key to the OMIM reference identification numbers isprovided in Table 5.

Table 1B.2

Column 5 of Table 1B.2, “Tissue Distribution” shows the expressionprofile of tissue, cells, and/or cell line libraries which express thepolynucleotides of the invention. The first code number shown in Table1B.2 column 5 (preceding the colon), represents the tissue/cell sourceidentifier code corresponding to the key provided in Table 4. Expressionof these polynucleotides was not observed in the other tissues and/orcell libraries tested. The second number in column 5 (following thecolon), represents the number of times a sequence corresponding to thereference polynucleotide sequence (e.g., SEQ ID NO:X) was identified inthe corresponding tissue/cell source. Those tissue/cell sourceidentifier codes in which the first two letters are “AR” designateinformation generated using DNA array technology. Utilizing thistechnology, cDNAs were amplified by PCR and then transferred, induplicate, onto the array. Gene expression was assayed throughhybridization of first strand cDNA probes to the DNA array. cDNA probeswere generated from total RNA extracted from a variety of differenttissues and cell lines. Probe synthesis was performed in the presence of³³P dCTP, using oligo(dT) to prime reverse transcription. Afterhybridization, high stringency washing conditions were employed toremove non-specific hybrids from the array. The remaining signal,emanating from each gene target, was measured using a Phosphorimager.Gene expression was reported as Phosphor Stimulating Luminescence (PSL)which reflects the level of phosphor signal generated from the probehybridized to each of the gene targets represented on the array. A localbackground signal subtraction was performed before the total signalgenerated from each array was used to normalize gene expression betweenthe different hybridizations. The value presented after “[array code]:”represents the mean of the duplicate values, following backgroundsubtraction and probe normalization. One of skill in the art couldroutinely use this information to identify normal and/or diseasedtissue(s) which show a predominant expression pattern of thecorresponding polynucleotide of the invention or to identifypolynucleotides which show predominant and/or specific tissue and/orcell expression.

Description of Table 1C

Table 1C summarizes additional polynucleotides encompassed by theinvention (including cDNA clones related to the sequences (Clone ID:),contig sequences (contig identifier (Contig ID:) contig nucleotidesequence identifiers (SEQ ID NO:X)), and genomic sequences (SEQ IDNO:B). The first column provides a unique clone identifier, “Clone ID:”,for a cDNA clone related to each contig sequence. The second columnprovides the sequence identifier, “SEQ ID NO:X”, for each contigsequence. The third column provides a unique contig identifier, “ContigID:” for each contig sequence. The fourth column, provides a BACidentifier “BAC ID NO:A” for the BAC clone referenced in thecorresponding row of the table. The fifth column provides the nucleotidesequence identifier, “SEQ ID NO:B” for a fragment of the BAC cloneidentified in column four of the corresponding row of the table. Thesixth column, “Exon From-To”, provides the location (i.e., nucleotideposition numbers) within the polynucleotide sequence of SEQ ID NO:Bwhich delineate certain polynucleotides of the invention that are alsoexemplary members of polynucleotide sequences that encode polypeptidesof the invention (e.g., polypeptides containing amino acid sequencesencoded by the polynucleotide sequences delineated in column six, andfragments and variants thereof).

Description of Table 1D

Table 1D: In preferred embodiments, the present invention encompasses amethod of detecting, preventing, diagnosing, prognosticating, treating,and/or ameliorating cardiovascular diseases or disorders; comprisingadministering to a patient in which such treatment, prevention, oramelioration is desired a protein, nucleic acid, or antibody of theinvention (or fragment or variant thereof) represented by Table 1A,Table 1B, and Table 1C, in an amount effective to detect, prevent,diagnose, prognosticate, treat, and/or ameliorate the disease ordisorder.

As indicated in Table 1D, the polynucleotides, polypeptides, agonists,or antagonists of the present invention (including antibodies) can beused in assays to test for one or more biological activities. If thesepolynucleotides and polypeptides do exhibit activity in a particularassay, it is likely that these molecules may be involved in the diseasesassociated with the biological activity. Thus, the polynucleotides orpolypeptides, or agonists or antagonists thereof (including antibodies)could be used to treat the associated disease.

Table 1D provides information related to biological activities forpolynucleotides and polypeptides of the invention (including antibodies,agonists, and/or antagonists thereof). Table 1D also providesinformation related to assays which may be used to test polynucleotidesand polypeptides of the invention (including antibodies, agonists,and/or antagonists thereof) for the corresponding biological activities.The first column (“Gene No.”) provides the gene number in theapplication for each clone identifier. The second column (“cDNA CloneID:”) provides the unique clone identifier for each clone as previouslydescribed and indicated in Tables 1A, 1B, and 1C. The third column (“AASEQ ID NO:Y”) indicates the Sequence Listing SEQ ID Number forpolypeptide sequences encoded by the corresponding cDNA clones (also asindicated in Tables 1A, 1B, and 2). The fourth column (“BiologicalActivity”) indicates a biological activity corresponding to theindicated polypeptides (or polynucleotides encoding said polypeptides).The fifth column (“Exemplary Activity Assay”) further describes thecorresponding biological activity and provides information pertaining tothe various types of assays which may be performed to test, demonstrate,or quantify the corresponding biological activity. Table 1D describesthe use of FMAT technology, inter alia, for testing or demonstratingvarious biological activities. Fluorometric microvolume assay technology(FMAT) is a fluorescence-based system which provides a means to performnonradioactive cell- and bead-based assays to detect activation of cellsignal transduction pathways. This technology was designed specificallyfor ligand binding and immunological assays. Using this technology,fluorescent cells or beads at the bottom of the well are detected aslocalized areas of concentrated fluorescence using a data processingsystem. Unbound flurophore comprising the background signal is ignored,allowing for a wide variety of homogeneous assays. FMAT technology maybe used for peptide ligand binding assays, immunofluorescence,apoptosis, cytotoxicity, and bead-based immunocapture assays. See,Miraglia S et. al., “Homogeneous cell and bead based assays forhighthroughput screening using flourometric microvolume assaytechnology,” Journal of Biomolecular Screening; 4:193-204 (1999). Inparticular, FMAT technology may be used to test, confirm, and/oridentify the ability of polypeptides (including polypeptide fragmentsand variants) to activate signal transduction pathways. For example,FMAT technology may be used to test, confirm, and/or identify theability of polypeptides to upregulate production of immunomodulatoryproteins (such as, for example, interleukins, GM-CSF, Rantes, and TumorNecrosis factors, as well as other cellular regulators (e.g. insulin)).

Table 1D also describes the use of kinase assays for testing,demonstrating, or quantifying biological activity. In this regard, thephosphorylation and de-phosphorylation of specific amino acid residues(e.g. Tyrosine, Serine, Threonine) on cell-signal transduction proteinsprovides a fast, reversible means for activation and de-activation ofcellular signal transduction pathways. Moreover, cell signaltransduction via phosphorylation/de-phosphorylation is crucial to theregulation of a wide variety of cellular processes (e.g. proliferation,differentiation, migration, apoptosis, etc.). Accordingly, kinase assaysprovide a powerful tool useful for testing, confirming, and/oridentifying polypeptides (including polypeptide fragments and variants)that mediate cell signal transduction events via proteinphosphorylation. See e.g., Forrer, P., Tamaskovic R., and Jaussi, R.“Enzyme-Linked Immunosorbent Assay for Measurement of JNK, ERK, and p38Kinase Activities” Biol. Chem. 379(8-9): 1101-1110 (1998).

Description of Table 1E

Table 1E: Polynucleotides encoding polypeptides of the present inventioncan be used in assays to test for one or more biological activities. Onesuch biological activity which may be tested includes the ability ofpolynucleotides and polypeptides of the invention to stimulateup-regulation or down-regulation of expression of particular genes andproteins. Hence, if polynucleotides and polypeptides of the presentinvention exhibit activity in altering particular gene and proteinexpression patterns, it is likely that these polynucleotides andpolypeptides of the present invention may be involved in, or capable ofeffecting changes in, diseases associated with the altered gene andprotein expression profiles. Hence, polynucleotides, polypeptides, orantibodies of the present invention could be used to treat saidassociated diseases.

TaqMan® assays may be performed to assess the ability of polynucleotides(and polypeptides they encode) to alter the expression pattern ofparticular “target” genes. TaqMan® reactions are performed to evaluatethe ability of a test agent to induce or repress expression of specificgenes in different cell types. TaqMan® gene expression quantificationassays (“TaqMan® assays”) are well known to, and routinely performed by,those of ordinary skill in the art. TaqMan® assays are performed in atwo step reverse transcription/polymerase chain reaction (RT-PCR). Inthe first (RT) step, cDNA is reverse transcribed from total RNA samplesusing random hexamer primers. In the second (PCR) step, PCR products aresynthesized from the cDNA using gene specific primers.

To quantify gene expression the Taqman® PCR reaction exploits the 5′nuclease activity of AmpliTaq Golds DNA Polymerase to cleave a Taqman®probe (distinct from the primers) during PCR. The Taqman® probe containsa reporter dye at the 5′-end of the probe and a quencher dye at the 3′end of the probe. When the probe is intact, the proximity of thereporter dye to the quencher dye results in suppression of the reporterfluorescence. During PCR, if the target of interest is present, theprobe specifically anneals between the forward and reverse primer sites.AmpliTaq Fold DNA Polymerase then cleaves the probe between the reporterand quencher when the probe hybridizes to the target, resulting inincreased fluorescence of the reporter (see FIG. 2). Accumulation of PCRproducts is detected directly by monitoring the increase in fluorescenceof the reporter dye.

After the probe fragments are displaced from the target, polymerizationof the strand continues. The 3′-end of the probe is blocked to preventextension of the probe during PCR. This process occurs in every cycleand does not interfere with the exponential accumulation of product. Theincrease in fluorescence signal is detected only if the target sequenceis complementary to the probe and is amplified during PCR. Because ofthese requirements, any nonspecific amplification is not detected.

For test sample preparation, vector controls or constructs containingthe coding sequence for the gene of interest are transfected into cells,such as for example 293T cells, and supernatants collected after 48hours. For cell treatment and RNA isolation, multiple primary humancells or human cell lines are used; such cells may include but are notlimited to, Normal Human Dermal Fibroblasts, Aortic Smooth Muscle, HumanUmbilical Vein Endothelial Cells, HepG2, Daudi, Jurkat, U937, Caco, andTHP-1 cell lines. Cells are plated in growth media and growth isarrested by culturing without media change for 3 days, or by switchingcells to low serum media and incubating overnight. Cells are treated for1, 6, or 24 hours with either vector control supernatant or samplesupernatant (or purified/partially purified protein preparations inbuffer). Total RNA is isolated; for example, by using Trizol extractionor by using the Ambion RNAqueous(TM)₄PCR RNA isolation system.Expression levels of multiple genes are analyzed using TAQMAN, andexpression in the test sample is compared to control vector samples toidentify genes induced or repressed. Each of the above describedtechniques are well known to, and routinely performed by, those ofordinary skill in the art.

Table 1E indicates particular disease classes and preferred indicationsfor which polynucleotides, polypeptides, or antibodies of the presentinvention may be used in detecting, diagnosing, preventing, treatingand/or ameliorating said diseases and disorders based on “target” geneexpression patterns which may be up- or down-regulated bypolynucleotides (and the encoded polypeptides) corresponding to eachindicated cDNA Clone ID (shown in Table 1E, Column 2).

Thus, in preferred embodiments, the present invention encompasses amethod of detecting, diagnosing, preventing, treating, and/orameliorating a disease or disorder listed in the “Disease Class” and/or“Preferred Indication” columns of Table 1E; comprising administering toa patient in which such detection, diagnosis, prevention, or treatmentis desired a protein, nucleic acid, or antibody of the invention (orfragment or variant thereof) in an amount effective to detect, diagnose,prevent, treat, or ameliorate the disease or disorder. The first andsecond columns of Table 1D show the “Gene No.” and “cDNA Clone ID No.”,respectively, indicating certain nucleic acids and proteins (orantibodies against the same) of the invention (including polynucleotide,polypeptide, and antibody fragments or variants thereof) that may beused in detecting, diagnosing, preventing, treating, or ameliorating thedisease(s) or disorder(s) indicated in the corresponding row in the“Disease Class” or “Preferred Indication” Columns of Table 1E.

In another embodiment, the present invention also encompasses methods ofdetecting, diagnosing, preventing, treating, or ameliorating a diseaseor disorder listed in the “Disease Class” or “Preferred Indication”Columns of Table 1E; comprising administering to a patient combinationsof the proteins, nucleic acids, or antibodies of the invention (orfragments or variants thereof), sharing similar indications as shown inthe corresponding rows in the “Disease Class” or “Preferred Indication”Columns of Table 1E.

The “Disease Class” Column of Table 1E provides a categorizeddescriptive heading for diseases, disorders, and/or conditions (morefully described below) that may be detected, diagnosed, prevented,treated, or ameliorated by a protein, nucleic acid, or antibody of theinvention (or fragment or variant thereof).

The “Preferred Indication” Column of Table 1E describes diseases,disorders, and/or conditions that may be detected, diagnosed, prevented,treated, or ameliorated by a protein, nucleic acid, or antibody of theinvention (or fragment or variant thereof).

The “Cell Line” and “Exemplary Targets” Columns of Table 1E indicateparticular cell lines and target genes, respectively, which may showaltered gene expression patterns (i.e., up- or down-regulation of theindicated target gene) in Taqman assays, performed as described above,utilizing polynucleotides of the cDNA Clone ID shown in thecorresponding row. Alteration of expression patterns of the indicated“Exemplary Target” genes is correlated with a particular “Disease Class”and/or “Preferred Indication” as shown in the corresponding row underthe respective column headings.

The “Exemplary Accessions” Column indicates GenBank Accessions(available online through the National Center for BiotechnologyInformation (NCBI) at http://www.ncbi.nlm.nih.gov/) which correspond tothe “Exemplary Targets” shown in the adjacent row.

The recitation of “Cancer” in the “Disease Class” Column indicates thatthe corresponding nucleic acid and protein, or antibody against thesame, of the invention (or fragment or variant thereof) may be used forexample, to detect, diagnose, prevent, treat, and/or ameliorateneoplastic diseases and/or disorders (e.g., leukemias, cancers, etc., asdescribed below under “Hyperproliferative Disorders”).

The recitation of “Immune” in the “Disease Class” column indicates thatthe corresponding nucleic acid and protein, or antibody against thesame, of the invention (or fragment or variant thereof), may be used forexample, to detect, diagnose, prevent, treat, and/or ameliorate diseasesand/or disorders relating to neoplastic diseases (e.g., as describedbelow under “Hyperproliferative Disorders”), blood disorders (e.g., asdescribed below under “Immune Activity” “Cardiovascular Disorders”and/or “Blood-Related Disorders”), and infections (e.g., as describedbelow under “Infectious Disease”).

The recitation of “Angiogenesis” in the “Disease Class” column indicatesthat the corresponding nucleic acid and protein, or antibody against thesame, of the invention (or fragment or variant thereof), may be used forexample, to detect, diagnose, treat, prevent, and/or ameliorate diseasesand/or disorders relating to neoplastic diseases (e.g., as describedbelow under “Hyperproliferative Disorders”), diseases and/or disordersof the cardiovascular system (e.g., as described below under“Cardiovascular Disorders”), diseases and/or disorders involvingcellular and genetic abnormalities (e.g., as described below under“Diseases at the Cellular Level”), diseases and/or disorders involvingangiogenesis (e.g., as described below under “Anti-AngiogenesisActivity”), to promote or inhibit cell or tissue regeneration (e.g., asdescribed below under “Regeneration”), or to promote wound healing(e.g., as described below under “Wound Healing and Epithelial CellProliferation”).

The recitation of “Diabetes” in the “Disease Class” column indicatesthat the corresponding nucleic acid and protein, or antibody against thesame, of the invention (or fragment or variant thereof), may be used forexample, to detect, diagnose, treat, prevent, and/or ameliorate diabetes(including diabetes mellitus types I and II), as well as diseases and/ordisorders associated with, or consequential to, diabetes (e.g. asdescribed below under “Endocrine Disorders,” “Renal Disorders,” and“Gastrointestinal Disorders”).

Description of Table 2

Table 2 summarizes homology and features of some of the polypeptides ofthe invention. The first column provides a unique clone identifier,“Clone ID:”, corresponding to a cDNA clone disclosed in Table 1A orTable 1B. The second column provides the unique contig identifier,“Contig ID:” corresponding to contigs in Table 1B and allowing forcorrelation with the information in Table 1B. The third column providesthe sequence identifier, “SEQ ID NO:X”, for the contig polynucleotidesequence. The fourth column provides the analysis method by which thehomology/identity disclosed in the Table was determined. Comparisonswere made between polypeptides encoded by the polynucleotides of theinvention and either a non-redundant protein database (herein referredto as “NR”), or a database of protein families (herein referred to as“PFAM”) as further described below. The fifth column provides adescription of the PFAM/NR hit having a significant match to apolypeptide of the invention. Column six provides the accession numberof the PFAM/NR hit disclosed in the fifth column. Column seven,“Score/Percent Identity”, provides a quality score or the percentidentity, of the hit disclosed in columns five and six. Columns 8 and 9,“NT From” and “NT To” respectively, delineate the polynucleotides in“SEQ ID NO:X” that encode a polypeptide having a significant match tothe PFAM/NR database as disclosed in the fifth and sixth columns. Inspecific embodiments polypeptides of the invention comprise, oralternatively consist of, an amino acid sequence encoded by apolynucleotide in SEQ ID NO:X as delineated in columns 8 and 9, orfragments or variants thereof.

Description of Table 3

Table 3 provides polynucleotide sequences that may be disclaimedaccording to certain embodiments of the invention. The first columnprovides a unique clone identifier, “Clone ID”, for a cDNA clone relatedto contig sequences disclosed in Table 1B. The second column providesthe sequence identifier, “SEQ ID NO:X”, for contig sequences disclosedin Table 1A and/or Table 1B. The third column provides the unique contigidentifier, “Contig ID:”, for contigs disclosed in Table 1B. The fourthcolumn provides a unique integer ‘a’ where ‘a’ is any integer between 1and the final nucleotide minus 15 of SEQ ID NO:X, and the fifth columnprovides a unique integer ‘b’ where ‘b’ is any integer between 15 andthe final nucleotide of SEQ ID NO:X, where both a and b correspond tothe positions of nucleotide residues shown in SEQ ID NO:X, and where bis greater than or equal to a +14. For each of the polynucleotides shownas SEQ ID NO:X, the uniquely defined integers can be substituted intothe general formula of a-b, and used to describe polynucleotides whichmay be preferably excluded from the invention. In certain embodiments,preferably excluded from the invention are at least one, two, three,four, five, ten, or more of the polynucleotide sequence(s) having theaccession number(s) disclosed in the sixth column of this Table(including for example, published sequence in connection with aparticular BAC clone). In further embodiments, preferably excluded fromthe invention are the specific polynucleotide sequence(s) contained inthe clones corresponding to at least one, two, three, four, five, ten,or more of the available material having the accession numbersidentified in the sixth column of this Table (including for example, theactual sequence contained in an identified BAC clone).

Description of Table 4

Table 4 provides a key to the tissue/cell source identifier codedisclosed in Table 1B.2, column 5. Column 1 provides the tissue/cellsource identifier code disclosed in Table 1B.2, Column 5. Columns 2-5provide a description of the tissue or cell source. Note that“Description” and “Tissue” sources (i.e. columns 2 and 3) having theprefix “a_” indicates organs, tissues, or cells derived from “adult”sources. Codes corresponding to diseased tissues are indicated in column6 with the word “disease.” The use of the word “disease” in column 6 isnon-limiting. The tissue or cell source may be specific (e.g. aneoplasm), or may be disease-associated (e.g., a tissue sample from anormal portion of a diseased organ). Furthermore, tissues and/or cellslacking the “disease” designation may still be derived from sourcesdirectly or indirectly involved in a disease state or disorder, andtherefore may have a further utility in that disease state or disorder.In numerous cases where the tissue/cell source is a library, column 7identifies the vector used to generate the library.

Description of Table 5

Table 5 provides a key to the OMIM reference identification numbersdisclosed in Table 1B.1. OMIM reference identification numbers(Column 1) were derived from Online Mendelian Inheritance in Man (OnlineMendelian Inheritance in Man, OMIM. McKusick-Nathans Institute forGenetic Medicine, Johns Hopkins University (Baltimore, Md.) and NationalCenter for Biotechnology Information, National Library of Medicine,(Bethesda, Md.) 2000. World Wide Web URL:http://www.ncbi.nlm.nih.gov/omim/). Column 2 provides diseasesassociated with the cytologic band disclosed in Table 1B. 1, asdetermined using the Morbid Map database.

Description of Table 6

Table 6 summarizes some of the ATCC Deposits, Deposit dates, and ATCCdesignation numbers of deposits made with the ATCC in connection withthe present application. These deposits were made in addition to thosedescribed in the Table 1A.

Description of Table 7

Table 7 shows the cDNA libraries sequenced, and ATCC designation numbersand vector information relating to these cDNA libraries.

The first column shows the first four letters indicating the Libraryfrom which each library clone was derived. The second column indicatesthe catalogued tissue description for the corresponding libraries. Thethird column indicates the vector containing the corresponding clones.The fourth column shows the ATCC deposit designation for each libraryclone as indicated by the deposit information in Table 6.

Definitions

The following definitions are provided to facilitate understanding ofcertain terms used throughout this specification.

In the present invention, “isolated” refers to material removed from itsoriginal environment (e.g., the natural environment if it is naturallyoccurring), and thus is altered “by the hand of man” from its naturalstate. For example, an isolated polynucleotide could be part of a vectoror a composition of matter, or could be contained within a cell, andstill be “isolated” because that vector, composition of matter, orparticular cell is not the original environment of the polynucleotide.The term “isolated” does not refer to genomic or cDNA libraries, wholecell total or mRNA preparations, genomic DNA preparations (includingthose separated by electrophoresis and transferred onto blots), shearedwhole cell genomic DNA preparations or other compositions where the artdemonstrates no distinguishing features of the polynucleotide/sequencesof the present invention.

In the present invention, a “secreted” protein refers to those proteinscapable of being directed to the ER, secretory vesicles, or theextracellular space as a result of a signal sequence, as well as thoseproteins released into the extracellular space without necessarilycontaining a signal sequence. If the secreted protein is released intothe extracellular space, the secreted protein can undergo extracellularprocessing to produce a “mature” protein. Release into the extracellularspace can occur by many mechanisms, including exocytosis and proteolyticcleavage.

As used herein, a “polynucleotide” refers to a molecule having a nucleicacid sequence encoding SEQ ID NO:Y or a fragment or variant thereof(e.g., the polypeptide delinated in columns fourteen and fifteen ofTable 1A); a nucleic acid sequence contained in SEQ ID NO:X (asdescribed in column 5 of Table 1A and/or Table 1B) or the complementthereof; a cDNA sequence contained in Clone ID: (as described in column2 of Table 1A and/or Table 1B and contained within a library depositedwith the ATCC); a nucleotide sequence encoding the polypeptide encodedby a nucleotide sequence in SEQ ID NO:B as defined in column 6 (EXONFrom-To) of Table 1C or a fragment or variant thereof; or a nucleotidecoding sequence in SEQ ID NO:B as defined in column 6 of Table 1C or thecomplement thereof. For example, the polynucleotide can contain thenucleotide sequence of the full length cDNA sequence, including the 5′and 3′ untranslated sequences, the coding region, as well as fragments,epitopes, domains, and variants of the nucleic acid sequence. Moreover,as used herein, a “polypeptide” refers to a molecule having an aminoacid sequence encoded by a pblynucleotide of the invention as broadlydefined (obviously excluding poly-Phenylalanine or poly-Lysine peptidesequences which result from translation of a polyA tail of a sequencecorresponding to a cDNA).

In the present invention, “SEQ ID NO:X” was often generated byoverlapping sequences contained in multiple clones (contig analysis). Arepresentative clone containing all or most of the sequence for SEQ IDNO:X is deposited at Human Genome Sciences, Inc. (HGS) in a cataloguedand archived library. As shown, for example, in Table 1B, each clone isidentified by a cDNA Clone ID (identifier generally referred to hereinas Clone ID:). Each Clone ID is unique to an individual clone and theClone ID is all the information needed to retrieve a given clone fromthe HGS library. Table 7 provides a list of the deposited cDNAlibraries. One can use the Clone ID: to determine the library source byreference to Tables 6 and 7. Table 7 lists the deposited cDNA librariesby name and links each library to an ATCC Deposit. Library names containfour characters, for example, “HTWE.” The name of a cDNA clone (CloneID) isolated from that library begins with the same four characters, forexample “HTWEP07”. As mentioned below, Table 1A and/or Table 1Bcorrelates the Clone ID names with SEQ ID NO:X. Thus, starting with anSEQ ID NO:X, one can use Tables 1A, 1B, 6, 7, and 9 to determine thecorresponding Clone ID, which library it came from and which ATCCdeposit the library is contained in. Furthermore, it is possible toretrieve a given cDNA clone from the source library by techniques knownin the art and described elsewhere herein. The ATCC is located at 10801University Boulevard, Manassas, Va. 20110-2209, USA. The ATCC depositswere made pursuant to the terms of the Budapest Treaty on theinternational recognition of the deposit of microorganisms for thepurposes of patent procedure.

In specific embodiments, the polynucleotides of the invention are atleast 15, at least 30, at least 50, at least 100, at least 125, at least500, or at least 1000 continuous nucleotides but are less than or equalto 300 kb, 200 kb, 100 kb, 50 kb, 15 kb, 10 kb, 7.5 kb, 5 kb, 2.5 kb,2.0 kb, or 1 kb, in length. In a further embodiment, polynucleotides ofthe invention comprise a portion of the coding sequences, as disclosedherein, but do not comprise all or a portion of any intron. In anotherembodiment, the polynucleotides comprising coding sequences do notcontain coding sequences of a genomic flanking gene (i.e., 5′ or 3′ tothe gene of interest in the genome). In other embodiments, thepolynucleotides of the invention do not contain the coding sequence ofmore than 1000, 500, 250, 100, 50, 25, 20, 15, 10, 5, 4, 3, 2, or 1genomic flanking gene(s).

A “polynucleotide” of the present invention also includes thosepolynucleotides capable of hybridizing, under stringent hybridizationconditions, to sequences contained in SEQ ID NO:X, or the complementthereof (e.g., the complement of any one, two, three, four, or more ofthe polynucleotide fragments described herein), the polynucleotidesequence delineated in columns 7 and 8 of Table 1A or the complementthereof, the polynucleotide sequence delineated in columns 8 and 9 ofTable 2 or the complement thereof, and/or cDNA sequences contained inClone ID: (e.g., the complement of any one, two, three, four, or more ofthe polynucleotide fragments, or the cDNA clone within the pool of cDNAclones deposited with the ATCC, described herein), and/or thepolynucleotide sequence delineated in column 6 of Table 1C or thecomplement thereof. “Stringent hybridization conditions” refers to anovernight incubation at 42 degree C. in a solution comprising 50%formamide, 5×SSC (750 mM NaCl, 75 mM trisodium citrate), 50 mM sodiumphosphate (pH 7.6), 5× Denhardt's solution, 10% dextran sulfate, and 20μg/ml denatured, sheared salmon sperm DNA, followed by washing thefilters in 0.1×SSC at about 65 degree C.

Also contemplated are nucleic acid molecules that hybridize to thepolynucleotides of the present invention at lower stringencyhybridization conditions. Changes in the stringency of hybridization andsignal detection are primarily accomplished through the manipulation offormamide concentration (lower percentages of formamide result inlowered stringency); salt conditions, or temperature. For example, lowerstringency conditions include an overnight incubation at 37 degree C. ina solution comprising 6×SSPE (20×SSPE=3M NaCl; 0.2M NaH₂PO₄; 0.02M EDTA,pH 7.4), 0.5% SDS, 30% formamide, 100 ug/ml salmon sperm blocking DNA;followed by washes at 50 degree C. with 1×SSPE, 0.1% SDS. In addition,to achieve even lower stringency, washes performed following stringenthybridization can be done at higher salt concentrations (e.g. 5×SSC).

Note that variations in the above conditions may be accomplished throughthe inclusion and/or substitution of alternate blocking reagents used tosuppress background in hybridization experiments. Typical blockingreagents include Denhardt's reagent, BLOTTO, heparin, denatured salmonsperm DNA, and commercially available proprietary formulations. Theinclusion of specific blocking reagents may require modification of thehybridization conditions described above, due to problems withcompatibility.

Of course, a polynucleotide which hybridizes only to polyA+ sequences(such as any 3′ terminal polyA+ tract of a cDNA shown in the sequencelisting), or to a complementary stretch of T (or U) residues, would notbe included in the definition of “polynucleotide,” since such apolynucleotide would hybridize to any nucleic acid molecule containing apoly (A) stretch or the complement thereof (e.g., practically anydouble-stranded cDNA clone generated using oligo dT as a primer).

The polynucleotide of the present invention can be composed of anypolyribonucleotide or polydeoxribonucleotide, which may be unmodifiedRNA or DNA or modified RNA or DNA. For example, polynucleotides can becomposed of single- and double-stranded DNA, DNA that is a mixture ofsingle- and double-stranded regions, single- and double-stranded RNA,and RNA that is mixture of single- and double-stranded regions, hybridmolecules comprising DNA and RNA that may be single-stranded or, moretypically, double-stranded or a mixture of single- and double-strandedregions. In addition, the polynucleotide can be composed oftriple-stranded regions comprising RNA or DNA or both RNA and DNA. Apolynucleotide may also contain one or more modified bases or DNA or RNAbackbones modified for stability or for other reasons. “Modified” basesinclude, for example, tritylated bases and unusual bases such asinosine. A variety of modifications can be made to DNA and RNA; thus,“polynucleotide” embraces chemically, enzymatically, or metabolicallymodified forms.

In specific embodiments, the polynucleotides of the invention are atleast 15, at least 30, at least 50, at least 100, at least 125, at least500, or at least 1000 continuous nucleotides but are less than or equalto 300 kb, 200 kb, 100 kb, 50 kb, 15 kb, 10 kb, 7.5 kb, 5 kb, 2.5 kb,2.0 kb, or 1 kb, in length. In a further embodiment, polynucleotides ofthe invention comprise a portion of the coding sequences, as disclosedherein, but do not comprise all or a portion of any intron. In anotherembodiment, the polynucleotides comprising coding sequences do notcontain coding sequences of a genomic flanking gene (i.e., 5′ or 3′ tothe gene of interest in the genome). In other embodiments, thepolynucleotides of the invention do not contain the coding sequence ofmore than 1000, 500, 250, 100, 50; 25, 20, 15, 10, 5, 4, 3, 2, or 1genomic flanking gene(s).

“SEQ ID NO:X” refers to a polynucleotide sequence described in column 5of Table 1A, while “SEQ ID NO:Y” refers to a polypeptide sequencedescribed in column 10 of Table 1A. SEQ ID NO:X is identified by aninteger specified in column 6 of Table 1A. The polypeptide sequence SEQID NO:Y is a translated open reading frame (ORF) encoded bypolynucleotide SEQ ID NO:X. The polynucleotide sequences are shown inthe sequence listing immediately followed by all of the polypeptidesequences. Thus, a polypeptide sequence corresponding to polynucleotidesequence SEQ ID NO:2 is the first polypeptide sequence shown in thesequence listing. The second polypeptide sequence corresponds to thepolynucleotide sequence shown as SEQ ID NO:3, and so on.

The polypeptide of the present invention can be composed of amino acidsjoined to each other by peptide bonds or modified peptide bonds, i.e.,peptide isosteres, and may contain amino acids other than the 20gene-encoded amino acids. The polypeptides may be modified by eithernatural processes, such as posttranslational processing, or by chemicalmodification techniques which are well known in the art. Suchmodifications are well described in basic texts and in more detailedmonographs, as well as in a voluminous research literature.Modifications can occur anywhere in a polypeptide, including the peptidebackbone, the amino acid side-chains and the amino or carboxyl termini.It will be appreciated that the same type of modification may be presentin the same or varying degrees at several sites in a given polypeptide.Also, a given polypeptide may contain many types of modifications.Polypeptides may be branched, for example, as a result ofubiquitination, and they may be cyclic, with or without branching.Cyclic, branched, and branched cyclic polypeptides may result fromposttranslation natural processes or may be made by synthetic methods.Modifications include acetylation, acylation, ADP-ribosylation,amidation, covalent attachment of flavin, covalent attachment of a hememoiety, covalent attachment of a nucleotide or nucleotide derivative,covalent attachment of a lipid or lipid derivative, covalent attachmentof phosphotidylinositol, cross-linking, cyclization, disulfide bondformation, demethylation, formation of covalent cross-links, formationof cysteine, formation of pyroglutamate, formylation,gamma-carboxylation, glycosylation, GPI anchor formation, hydroxylation,iodination, methylation, myristoylation, oxidation, pegylation,proteolytic processing, phosphorylation, prenylation, racemization,selenoylation, sulfation, transfer-RNA mediated addition of amino acidsto proteins such as arginylation, and ubiquitination. (See, forinstance, PROTEINS—STRUCTURE AND MOLECULAR PROPERTIES, 2nd Ed., T. E.Creighton, W. H. Freeman and Company, New York (1993); POSTTRANSLATIONALCOVALENT MODIFICATION OF PROTEINS, B. C. Johnson, Ed., Academic Press,New York, pgs. 1-12 (1983); Seifter et al., Meth. Enzymol. 182:626-646(1990); Rattan et al., Ann. N.Y. Acad. Sci. 663:48-62 (1992)).

“SEQ ID NO:X” refers to a polynucleotide sequence described, forexample, in Tables 1A, Table 1B, or Table 2, while “SEQ ID NO:Y” refersto a polypeptide sequence described in column 11 of Table 1A and orTable 1B. SEQ ID NO:X is identified by an integer specified in Table 1B.The polypeptide sequence SEQ ID NO:Y is a translated open reading frame(ORE) encoded by polynucleotide SEQ ID NO:X. “Clone ID:” refers to acDNA clone described in column 2 of Table IA and/or Table 1B.

“A polypeptide having functional activity” refers to a polypeptidecapable of displaying one or more known functional activities associatedwith a full-length (complete) protein. Such functional activitiesinclude, but are not limited to, biological activity (e.g. activityuseful in treating, preventing and/or ameliorating cardiovasculardiseases and disorders), antigenicity (ability to bind [or compete witha polypeptide for binding] to an anti-polypeptide antibody),immunogenicity (ability to generate antibody which binds to a specificpolypeptide of the invention), ability to form multimers withpolypeptides of the invention, and ability to bind to a receptor orligand for a polypeptide.

The polypeptides of the invention can be assayed for functional activity(e.g. biological activity) using or routinely modifying assays known inthe art, as well as assays described herein. Specifically, one of skillin the art may routinely assay secreted polypeptides (includingfragments and variants) of the invention for activity using assays asdescribed in the examples section below.

“A polypeptide having biological activity” refers to a polypeptideexhibiting activity similar to, but not necessarily identical to, anactivity of a polypeptide of the present invention, including matureforms, as measured in a particular biological assay, with or withoutdose dependency. In the case where dose dependency does exist, it neednot be identical to that of the polypeptide, but rather substantiallysimilar to the dose-dependence in a given activity as compared to thepolypeptide of the present invention (i.e., the candidate polypeptidewill exhibit greater activity or not more than about 25-fold less and,preferably, not more than about tenfold less activity, and mostpreferably, not more than about three-fold less activity relative to thepolypeptide of the present invention).

Tables

Table 1A

Table 1A summarizes information concerning certain polypnucleotides andpolypeptides of the invention. The first column provides the gene numberin the application for each clone identifier. The second column providesa unique clone identifier, “Clone ID:”, for a cDNA clone related to eachcontig sequence disclosed in Table 1A. Third column, the cDNA Clonesidentified in the second column were deposited as indicated in the thirdcolumn (i.e. by ATCC Deposit No:Z and deposit date). Some of thedeposits contain multiple different clones corresponding to the samegene. In the fourth column, “Vector” refers to the type of vectorcontained in the corresponding cDNA Clone identified in the secondcolumn. In the fifth column, the nucleotide sequence identified as “NTSEQ ID NO:X” was assembled from partially homologous (“overlapping”)sequences obtained from the corresponding cDNA clone identified in thesecond column and, in some cases, from additional related cDNA clones.The overlapping sequences were assembled into a single contiguoussequence of high redundancy (usually three to five overlapping sequencesat each nucleotide position), resulting in a final sequence identifiedas SEQ ID NO:X. In the sixth column, “Total NT Seq.” refers to the totalnumber of nucleotides in the contig sequence identified as SEQ ID NO:X.”The deposited clone may contain all or most of these sequences,reflected by the nucleotide position indicated as “5′ NT of Clone Seq.”(seventh column) and the “3′ NT of Clone Seq.” (eighth column) of SEQ IDNO:X. In the ninth column, the nucleotide position of SEQ ID NO:X of theputative start codon (methionine) is identified as “5′ NT of StartCodon.” Similarly, in column ten, the nucleotide position of SEQ ID NO:Xof the predicted signal sequence is identified as “5′ NT of First AA ofSignal Pep.” In the eleventh column, the translated amino acid sequence,beginning with the methionine, is identified as “AA SEQ ID NO:Y,”although other reading frames can also be routinely translated usingknown molecular biology techniques. The polypeptides produced by thesealternative open reading frames are specifically contemplated by thepresent invention.

In the twelfth and thirteenth columns of Table 1A, the first and lastamino acid position of SEQ ID NO:Y of the predicted signal peptide isidentified as “First AA of Sig Pep” and “Last AA of Sig Pep.” In thefourteenth column, the predicted first amino acid position of SEQ IDNO:Y of the secreted portion is identified as “Predicted First AA ofSecreted Portion”. The amino acid position of SEQ ID NO:Y of the lastamino acid encoded by the open reading frame is identified in thefifteenth column as “Last AA of ORF”.

SEQ ID NO:X (where X may be any of the polynucleotide sequencesdisclosed in the sequence listing) and the translated SEQ ID NO:Y (whereY may be any of the polypeptide sequences disclosed in the sequencelisting) are sufficiently accurate and otherwise suitable for a varietyof uses well known in the art and described further below. For instance,SEQ ID NO:X is useful for designing nucleic acid hybridization probesthat will detect nucleic acid sequences contained in SEQ ID NO:X or thecDNA contained in the deposited clone. These probes will also hybridizeto nucleic acid molecules in biological samples, thereby enabling avariety of forensic and diagnostic methods of the invention. Similarly,polypeptides identified from SEQ ID NO:Y may be used, for example, togenerate antibodies which bind specifically to proteins containing thepolypeptides and the secreted proteins encoded by the cDNA clonesidentified in Table 1A and/or elsewhere herein

Nevertheless, DNA sequences generated by sequencing reactions cancontain sequencing errors. The errors exist as misidentifiednucleotides, or as insertions or deletions of nucleotides in thegenerated DNA sequence. The erroneously inserted or deleted nucleotidescause frame shifts in the reading frames of the predicted amino acidsequence. In these cases, the predicted amino acid sequence divergesfrom the actual amino acid sequence, even though the generated DNAsequence may be greater than 99.9% identical to the actual DNA sequence(for example, one base insertion or deletion in an open reading frame ofover 1000 bases).

Accordingly, for those applications requiring precision in thenucleotide sequence or the amino acid sequence, the present inventionprovides not only the generated nucleotide sequence identified as SEQ IDNO:X, and the predicted translated amino acid sequence identified as SEQID NO:Y, but also a sample of plasmid DNA containing a human cDNA of theinvention deposited with the ATCC, as set forth in Table 1A. Thenucleotide sequence of each deposited plasmid can readily be determinedby sequencing the deposited plasmid in accordance with known methods

The predicted amino acid sequence can then be verified from suchdeposits. Moreover, the amino acid sequence of the protein encoded by aparticular plasmid can also be directly determined by peptide sequencingor by expressing the protein in a suitable host cell containing thedeposited human cDNA, collecting the protein, and determining itssequence.

Also provided in Table 1A is the name of the vector which contains thecDNA plasmid. Each vector is routinely used in the art. The followingadditional information is provided for convenience.

Vectors Lambda Zap (U.S. Pat. Nos. 5,128,256 and 5,286,636), Uni-Zap XR(U.S. Pat. Nos. 5,128,256 and 5,286,636), Zap Express (U.S. Pat. Nos.5,128,256 and 5,286,636), pBluescript (pBS) (Short, J. M. et al.,Nucleic Acids Res. 16:7583-7600 (1988); Alting-Mees, M. A. and Short, J.M., Nucleic Acids Res. 17:9494 (1989)) and pBK (Alting-Mees, M. A. etal., Strategies 5:58-61 (1992)) are commercially available fromStratagene Cloning Systems, Inc., 11011 N. Torrey Pines Road, La Jolla,Calif., 92037. pBS contains an ampicillin resistance gene and pBKcontains a neomycin resistance gene. Phagemid pBS may be excised fromthe Lambda Zap and Uni-Zap XR vectors, and phagemid pBK may be excisedfrom the Zap Express vector. Both phagemids may be transformed into E.coli strain XL-1 Blue, also available from Stratagene

Vectors pSport1, pCMVSport 1.0, pCMVSport 2.0 and pCMVSport 3.0, wereobtained from Life Technologies, Inc., P.O. Box 6009, Gaithersburg, Md.20897. All Sport vectors contain an ampicillin resistance gene and maybe transformed into E. coli strain DH10B, also available from LifeTechnologies. See, for instance, Gruber, C. E., et al., Focus 15:59(1993). Vector lafinid BA (Bento Soares, Columbia University, New York,N.Y.) contains an ampicillin resistance gene and can be transformed intoE. coli strain XL-1 Blue. Vector pCR®2.1, which is available fromInvitrogen, 1600 Faraday Avenue, Carlsbad, Calif. 92008, contains anampicillin resistance gene and may be transformed into E. coli strainDH10B, available from Life Technologies. See, for instance, Clark, J.M., Nuc. Acids Res. 16:9677-9686 (1988) and Mead, D. et al.,Bio/Technology 9: (1991).

The present invention also relates to the genes corresponding to SEQ IDNO:X, SEQ ID NO:Y, and/or a deposited cDNA (cDNA Clone ID). Thecorresponding gene can be isolated in accordance with known methodsusing the sequence information disclosed herein. Such methods include,but are not limited to, preparing probes or primers from the disclosedsequence and identifying or amplifying the corresponding gene fromappropriate sources of genomic material.

Also provided in the present invention are allelic variants, orthologs,and/or species homologs. Procedures known in the art can be used toobtain full-length genes, allelic variants, splice variants, full-lengthcoding portions, orthologs, and/or species homologs of genescorresponding to SEQ ID NO:X and SEQ ID NO:Y using information from thesequences disclosed herein or the clones deposited with the ATCC. Forexample, allelic variants and/or species homologs may be isolated andidentified by making suitable probes or primers from the sequencesprovided herein and screening a suitable nucleic acid source for allelicvariants and/or the desired homologue.

The present invention provides a polynucleotide comprising, oralternatively consisting of, the nucleic acid sequence of SEQ ID NO:Xand/or a cDNA contained in ATCC Deposit No.Z. The present invention alsoprovides a polypeptide comprising, or alternatively, consisting of, thepolypeptide sequence of SEQ ID NO:Y, a polypeptide encoded by SEQ IDNO:X, and/or a polypeptide encoded by a cDNA contained in ATCC depositNo.Z. Polynucleotides encoding a polypeptide comprising, oralternatively consisting of the polypeptide sequence of SEQ ID NO:Y, apolypeptide encoded by SEQ ID NO:X and/or a polypeptide encoded by thecDNA contained in ATCC Deposit No.Z, are also encompassed by theinvention. The present invention further encompasses a polynucleotidecomprising, or alternatively consisting of the complement of the nucleicacid sequence of SEQ ID NO:X, and/or the complement of the coding strandof the cDNA contained in ATCC Deposit No.Z. TABLE 1A 5′ NT First LastATCC NT 5′ NT 3′ NT of First AA AA AA First AA Last Deposit SEQ Total ofof 5′ NT AA of SEQ of of of AA Gene cDNA No: Z and ID NT Clone Clone ofStart Signal ID Sig Sig Secreted of No. Clone ID Date Vector NO: X Seq.Seq. Seq. Codon Pep NO: Y Pep Pep Portion ORF 1 H6BSF56 203917 Uni-ZAPXR 11 605 44 605 83 264 1 6 7 141 Apr. 08, 1999 2 H6EDM64 203959 Uni-ZAPXR 12 2610 1275 2377 1448 1448 265 1 6 Apr. 26, 1999 3 H6EEC72 PTA-793Uni-ZAP XR 13 1493 1 1493 263 266 1 13 14 18 Sep. 27, 1999 4 H6EEU40203917 Uni-ZAP XR 14 951 1 951 175 175 267 1 27 28 47 Apr. 08, 1999 5HACAB68 203917 Uni-ZAP XR 15 1300 1 1300 135 135 268 1 26 27 78 Apr. 08,1999 6 HACBJ56 203979 Uni-ZAP XR 16 888 1 888 250 269 1 9 10 25 Apr. 29,1999 7 HADMB15 203979 pBluescript 17 330 1 330 238 270 1 11 12 20 Apr.29, 1999 8 HAGFS57 203979 Uni-ZAP XR 18 874 1 874 241 241 271 1 26 27 54Apr. 29, 1999 9 HAGHN57 203917 Uni-ZAP XR 19 2440 843 2440 900 900 272 110 Apr. 08, 1999 10 HAJAA47 203917 pCMVSport 20 1237 1 1237 192 273 1 1516 38 Apr. 08, 1999 3.0 11 HAJAY92 203959 pCMVSport 21 2345 1 2345 12 12274 1 20 21 94 Apr. 26, 1999 3.0 12 HAJBV67 PTA-181 pCMVSport 22 2536 12536 605 605 275 1 19 20 359 Jun. 07, 1999 3.0 13 HATCD80 203917 Uni-ZAPXR 23 1809 95 1809 296 296 276 1 23 24 37 Apr. 08, 1999 14 HATEH20203917 Uni-ZAP XR 24 850 1 850 93 93 277 1 19 20 42 Apr. 08, 1999 15HBAGD86 203917 pSport1 25 1713 293 1596 521 521 278 1 18 19 19 Apr. 08,1999 16 HBGBC29 203917 Uni-ZAP XR 26 1856 764 1829 1016 279 1 2 Apr. 08,1999 17 HBGNC72 PTA-793 Uni-ZAP XR 27 802 1 802 550 280 1 8 9 76 Sep.27, 1999 18 HBHAA05 203917 Uni-ZAP XR 28 690 1 690 110 281 1 16 17 58Apr. 08, 1999 19 HBHAA81 203959 Uni-ZAP XR 29 1647 1 1647 28 28 282 1 2425 203 Apr. 26, 1999 20 HBIAC29 203917 Uni-ZAP XR 30 1782 808 1545 10361036 283 1 24 25 29 Apr. 08, 1999 21 HBJAB02 203917 Uni-ZAP XR 31 1693 11665 84 84 284 1 27 28 34 Apr. 08, 1999 22 HBJAC40 203979 Uni-ZAP XR 321767 184 1729 329 285 1 13 Apr. 29, 1999 23 HBJCR46 203917 Uni-ZAP XR 333208 2270 3202 589 589 286 1 1 2 733 Apr. 08, 1999 24 HBJDW56 203917Uni-ZAP XR 34 637 1 637 121 287 1 8 Apr. 08, 1999 25 HBJEL16 203979Uni-ZAP XR 35 750 1 750 115 115 288 1 24 25 36 Apr. 29, 1999 26 HBJKD16203979 Uni-ZAP XR 36 1629 1 1629 78 78 289 1 18 19 31 Apr. 29, 1999 27HBMBM96 203917 pBluescript 37 1076 1 1076 170 290 1 4 Apr. 08, 1999 28HBMTM11 203917 Uni-ZAP XR 38 1639 1 1639 125 125 291 1 19 20 31 Apr. 08,1999 29 HBMUH74 PTA-181 Uni-ZAP XR 39 726 1 726 344 344 292 1 13 14 28Jun. 07, 1999 30 HBQAB79 203917 Lambda ZAP 40 1331 1 1331 190 190 293 111 Apr. 08, 1999 II 31 HBSAK32 PTA-181 Uni-ZAP XR 41 592 129 592 447 447294 1 27 28 48 Jun. 07, 1999 32 HBXCX15 203917 ZAP Express 42 1219 11219 1148 295 1 1 Apr. 08, 1999 33 HCDCY76 203917 Uni-ZAP XR 43 1392 6281392 860 296 1 17 18 35 Apr. 08, 1999 34 HCDDL48 203917 Uni-ZAP XR 44813 1 813 333 333 297 1 12 13 40 Apr. 08, 1999 35 HCE1G78 203917 Uni-ZAPXR 45 1896 1 1896 77 77 298 1 17 18 254 Apr. 08, 1999 36 HCE5F78 203917Uni-ZAP XR 46 1732 282 1732 566 299 1 8 9 32 Apr. 08, 1999 37 HCEDR26203917 Uni-ZAP XR 47 1419 1 1419 177 177 300 1 26 27 55 Apr. 08, 1999 38HCEEQ25 203917 Uni-ZAP XR 48 992 1 992 111 301 1 15 16 23 Apr. 08, 199939 HCEEU18 203917 Uni-ZAP XR 49 1229 1 1229 209 209 302 1 30 31 43 Apr.08, 1999 40 HCEGG08 203979 Uni-ZAP XR 50 2534 979 2025 1114 1114 303 115 16 27 Apr. 29, 1999 41 HCFLN88 203917 pSport1 51 1434 1 1434 101 101304 1 16 17 25 Apr. 08, 1999 42 HCHAB84 203979 pSport1 52 1359 62 1359304 305 1 23 24 147 Apr. 29, 1999 43 HCMSX51 203917 Uni-ZAP XR 53 2253334 2190 539 306 1 31 32 80 Apr. 08, 1999 44 HCNCO11 203917 Lambda ZAP54 746 1 746 101 101 307 1 14 Apr. 08, 1999 II 45 HCNSD29 PTA-181pBluescript 55 1728 1031 1633 1145 1145 308 1 19 20 31 Jun. 07, 1999 46HCQBH72 203917 Lambda ZAP 56 1796 776 1796 31 31 309 1 25 26 47 Apr. 08,1999 II 47 HCQCC96 203979 Lambda ZAP 57 2166 632 1455 782 782 310 1 2021 45 Apr. 29, 1999 II 48 HCUCF89 203917 ZAP Express 58 530 1 530 189189 311 1 18 19 29 Apr. 08, 1999 49 HCUCK44 203957 ZAP Express 59 1143578 1136 598 598 312 1 30 31 60 Apr. 26, 1999 50 HCUDD64 203917 ZAPExpress 60 402 150 389 256 256 313 1 35 36 49 Apr. 08, 1999 51 HCWAE64203917 ZAP Express 61 471 1 471 410 314 1 5 Apr. 08, 1999 52 HDPDI72PTA-794 pCMVSport 62 1550 1 1550 23 23 315 1 17 18 120 Sep. 27, 1999 3.053 HDPGE24 203960 pCMVSport 63 2625 1 2625 173 173 316 1 11 12 73 Apr.26, 1999 3.0 54 HDPIU94 203960 pCMVSport 64 2196 21 2196 208 208 317 121 22 23 Apr. 26, 1999 3.0 55 HDPIY31 PTA-793 pCMVSport 65 1978 1 1978268 268 318 1 16 17 35 Sep. 27, 1999 3.0 56 HDPOC24 203960 pCMVSport 661777 302 1725 418 418 319 1 23 24 133 Apr. 26, 1999 3.0 57 HDPOL37203960 pCMVSport 67 1489 1 1489 189 189 320 1 32 33 62 Apr. 26, 1999 3.058 HDPOO76 203960 pCMVSport 68 645 1 645 109 321 1 15 16 16 Apr. 26,1999 3.0 59 HDPPQ30 203960 pCMVSport 69 1063 1 1063 220 220 322 1 22 2338 Apr. 26, 1999 3.0 60 HDQHM36 PTA-181 pCMVSport 70 1547 1 1547 129 129323 1 18 19 48 Jun. 07, 1999 3.0 61 HE2CM39 203960 Uni-ZAP XR 71 566 1566 10 324 1 13 Apr. 26, 1999 62 HE2PO93 203960 Uni-ZAP XR 72 1323 6381323 770 770 325 1 27 28 42 Apr. 26, 1999 63 HE6FU11 203979 Uni-ZAP XR73 2000 1 1994 145 145 326 1 26 27 226 Apr. 29, 1999 64 HE6FV29 203960Uni-ZAP XR 74 1526 1 1526 210 210 327 1 18 19 33 Apr. 26, 1999 65HE9EA10 203960 Uni-ZAP XR 75 2114 1 2111 212 328 1 28 29 78 Apr. 26,1999 66 HEBCY54 203960 Uni-ZAP XR 76 1189 1 1189 172 172 329 1 24 25 118Apr. 26, 1999 67 HEBDF77 203960 Uni-ZAP XR 77 1820 1 1820 681 681 330 129 30 36 Apr. 26, 1999 68 HEBDQ91 203960 Uni-ZAP XR 78 1573 1007 15731211 331 1 29 30 41 Apr. 26, 1999 69 HEBFR46 203979 Uni-ZAP XR 79 1304 11304 200 200 332 1 26 27 29 Apr. 29, 1999 70 HEBGE07 203960 Uni-ZAP XR80 1867 1 1867 106 106 333 1 25 26 42 Apr. 26, 1999 71 HEGAU15 203960Uni-ZAP XR 81 1125 1 1125 59 59 334 1 30 31 34 Apr. 26, 1999 72 HEQBF89203960 pCMVSport 82 859 1 859 306 306 335 1 18 19 50 Apr. 26, 1999 3.073 HFCEI04 203960 Uni-ZAP XR 83 887 1 887 136 336 1 17 18 42 Apr. 26,1999 74 HFEAY59 203960 Uni-ZAP XR 84 1153 1 1153 154 154 337 1 24 25 40Apr. 26, 1999 75 HFIJA68 203979 pSport1 85 1157 1 1157 283 283 338 1 2223 43 Apr. 29, 1999 76 HFKEU12 203960 Uni-ZAP XR 86 1031 1 1031 6 6 3391 16 17 55 Apr. 26, 1999 77 HFPCZ55 203960 Uni-ZAP XR 87 2735 341 2735676 676 340 1 24 25 44 Apr. 26, 1999 78 HFTBM38 203960 Uni-ZAP XR 881941 322 1941 577 577 341 1 18 19 30 Apr. 26, 1999 79 HFTDH56 PTA-181Uni-ZAP XR 89 820 1 820 67 67 342 1 10 Jun. 07, 1999 80 HFVHW43 203960pBluescript 90 1233 1 1233 92 92 343 1 30 31 39 Apr. 26, 1999 81 HGBHP91203960 Uni-ZAP XR 91 1054 1 1054 50 344 1 14 15 52 Apr. 26, 1999 82HHEAK45 203960 pCMVSport 92 2014 87 1935 813 345 1 3 Apr. 26, 1999 3.083 HHEGS55 PTA-181 pCMVSport 93 594 2 594 159 159 346 1 16 17 36 Jun.07, 1999 3.0 84 HHEOW19 PTA-793 pCMVSport 94 1589 1 1589 183 183 347 118 19 64 Sep. 27, 1999 3.0 85 HHFFL34 203960 Uni-ZAP XR 95 2632 1 263242 42 348 1 21 22 223 Apr. 26, 1999 86 HHFFS40 203960 Uni-ZAP XR 96 18161 1816 37 37 349 1 18 19 47 Apr. 26, 1999 87 HHGCS78 203960 Lambda ZAP97 575 46 575 290 290 350 1 17 18 24 Apr. 26, 1999 II 88 HHGDT26 203960Lambda ZAP 98 1584 1 1584 181 181 351 1 8 Apr. 26, 1999 II 89 HHPFU28203960 Uni-ZAP XR 99 1838 1 1838 156 352 1 18 19 27 Apr. 26, 1999 90HHSBI06 203959 Uni-ZAP XR 100 1049 27 803 690 353 1 5 Apr. 26, 1999 91HHSBI65 203917 Uni-ZAP XR 101 1444 1 1431 62 62 354 1 17 18 55 Apr. 08,1999 92 HHSDI53 PTA-181 Uni-ZAP XR 102 1277 1 1277 221 221 355 1 14 1524 Jun. 07, 1999 93 HISAT67 203959 pSport1 103 2154 1061 2142 1239 1239356 1 35 36 56 Apr. 26, 1999 94 HJBCU75 203957 pBluescript 104 1009 11009 61 61 357 1 5 Apr. 26, 1999 SK− 95 HJMAA03 203957 pCMVSport 105 6651 665 527 358 1 9 Apr. 26, 1999 3.0 96 HJMAV41 PTA-181 pCMVSport 1061017 1 1017 207 207 359 1 27 Jun. 07, 1999 3.0 97 HJMAY90 203959pCMVSport 107 2886 2233 2886 2492 360 1 22 23 34 Apr. 26, 1999 3.0 98HJPBE39 203957 Uni-ZAP XR 108 1298 69 1298 170 361 1 18 Apr. 26, 1999 99HJPCH08 203959 Uni-ZAP XR 109 879 1 879 374 362 1 10 11 117 Apr. 26,1999 100 HKGBF25 203957 pSport1 110 2007 1 2007 261 261 363 1 18 19 36Apr. 26, 1999 101 HKIXC44 203957 pBluescript 111 788 343 750 572 572 3641 26 27 36 Apr. 26, 1999 102 HKTAB41 203957 Uni-ZAP XR 112 797 1 797 172172 365 1 10 Apr. 26, 1999 103 HLDBG17 PTA-181 pCMVSport 113 652 1 652184 184 366 1 23 24 41 Jun. 07, 1999 3.0 104 HLDQU79 203959 pCMVSport114 1488 1 1488 99 99 367 1 23 24 348 Apr. 26, 1999 3.0 104 HLDQU79203959 pCMVSport 253 3179 163 1474 75 75 506 1 29 30 348 Apr. 26, 19993.0 105 HLDRT09 203957 pCMVSport 115 721 254 665 522 522 368 1 20 21 66Apr. 26, 1999 3.0 106 HLHAP05 203957 Uni-ZAP XR 116 1842 12 1842 45 45369 1 14 Apr. 26, 1999 107 HLHCS23 203957 Uni-ZAP XR 117 1427 1 1427 2525 370 1 24 25 34 Apr. 26, 1999 108 HLIBO72 PTA-792 pCMVSport 1 118 17681 1768 167 167 371 1 46 47 127 Sep. 27, 1999 109 HLICE88 203957pCMVSport 1 119 840 401 824 708 372 1 2 Apr. 26, 1999 110 HLICO10 203957pCMVSport 1 120 903 1 903 441 441 373 1 23 24 72 Apr. 26, 1999 111HLJBS28 203957 pCMVSport 1 121 976 1 976 359 359 374 1 17 Apr. 26, 1999112 HLMJB64 203957 Lambda ZAP 122 804 1 804 12 12 375 1 29 30 49 Apr.26, 1999 II 113 HLWAV47 PTA-795 pCMVSport 123 2062 1 2062 200 200 376 129 30 32 Sep. 27, 1999 3.0 114 HLYDF73 203957 pSport1 124 626 1 626 363377 1 11 12 23 Apr. 26, 1999 115 HLYGE16 203957 pSport1 125 752 1 752406 406 378 1 17 18 73 Apr. 26, 1999 116 HLYGY91 203957 pSport1 126 6401 640 211 211 379 1 20 21 42 Apr. 26, 1999 117 HMCFH60 203957 Uni-ZAP XR127 443 1 443 211 211 380 1 17 18 48 Apr. 26, 1999 118 HMDAB29 203957Uni-ZAP XR 128 1190 1 1190 97 97 381 1 17 18 26 Apr. 26, 1999 119HMDAD44 203957 Uni-ZAP XR 129 1204 1 1204 135 135 382 1 8 Apr. 26, 1999120 HMEDI90 203957 Lambda ZAP 130 2276 362 2219 622 383 1 12 13 17 Apr.26, 1999 II 121 HMIAK10 203957 Uni-ZAP XR 131 1064 1 1064 195 195 384 122 23 31 Apr. 26, 1999 122 HMIBF07 203957 Uni-ZAP XR 132 1738 1 1738 229229 385 1 6 Apr. 26, 1999 123 HMICI80 203957 Uni-ZAP XR 133 1772 1 17721149 386 1 10 11 32 Apr. 26, 1999 124 HMJAK70 203957 pSport1 134 799 1799 273 273 387 1 10 Apr. 26, 1999 125 HMTAB77 203979 pCMVSport 135 38391 3839 769 769 388 1 24 25 48 Apr. 29, 1999 3.0 126 HMUAE26 203957pCMVSport 136 2000 660 2000 710 710 389 1 20 21 30 Apr. 26, 1999 3.0 127HMUAN45 203918 pCMVSport 137 2709 1 2709 239 239 390 1 25 26 227 Apr.08, 1999 3.0 128 HMVBC31 203957 pSport1 138 2556 1327 2546 1437 1437 3911 32 33 40 Apr. 26, 1999 129 HMWBL03 203957 Uni-ZAP XR 139 2596 80 2596137 137 392 1 1 2 397 Apr. 26, 1999 130 HMWCG28 203979 Uni-ZAP XR 140893 1 893 78 78 393 1 30 31 40 Apr. 29, 1999 131 HNECW49 203957 Uni-ZAPXR 141 489 1 463 316 316 394 1 20 21 58 Apr. 26, 1999 132 HNFCY57PTA-791 Uni-ZAP XR 142 2847 1 2847 317 317 395 1 10 11 629 Sep. 27, 1999133 HNFGR08 203957 Uni-ZAP XR 143 1436 1 1436 314 396 1 17 18 43 Apr.26, 1999 134 HNGAK51 203957 Uni-ZAP XR 144 915 1 915 248 248 397 1 23 2432 Apr. 26, 1999 135 HNGAM58 203957 Uni-ZAP XR 145 1156 1 1156 68 398 127 28 114 Apr. 26, 1999 136 HNGDX18 PTA-181 Uni-ZAP XR 146 1425 1 1425237 237 399 1 30 31 243 Jun. 07, 1999 136 HNGDX18 PTA-181 Uni-ZAP XR 2541411 1 1411 231 231 507 1 18 19 132 Jun. 07, 1999 137 HNGEQ75 203957Uni-ZAP XR 147 1029 1 1029 30 400 1 21 22 22 Apr. 26, 1999 138 HNGFR54203957 Uni-ZAP XR 148 495 1 495 73 401 1 36 37 52 Apr. 26, 1999 139HNGGA68 203957 Uni-ZAP XR 149 585 1 585 184 184 402 1 32 Apr. 26, 1999140 HNGHZ69 PTA-795 Uni-ZAP XR 150 1195 1 1195 25 403 1 9 Sep. 27, 1999141 HNGKT41 203959 Uni-ZAP XR 151 1048 1 1048 415 415 404 1 17 18 45Apr. 26, 1999 142 HNGMW45 203959 Uni-ZAP XR 152 1530 1 1530 452 452 4051 26 27 43 Apr. 26, 1999 143 HNGNO53 203959 Uni-ZAP XR 153 825 1 825 467467 406 1 15 16 34 Apr. 26, 1999 144 HNGPJ25 203959 Uni-ZAP XR 154 853129 853 544 544 407 1 20 21 25 Apr. 26, 1999 145 HNHFE71 203959 Uni-ZAPXR 155 903 1 903 598 598 408 1 21 Apr. 26, 1999 146 HNHGK22 203918Uni-ZAP XR 156 909 1 909 239 239 409 1 26 27 64 Apr. 08, 1999 147HNHKS19 203959 Uni-ZAP XR 157 790 1 790 192 192 410 1 26 27 41 Apr. 26,1999 148 HNHKV56 203959 Uni-ZAP XR 158 1653 1 1653 294 294 411 1 31 3266 Apr. 26, 1999 149 HOACG07 203959 Uni-ZAP XR 159 1298 772 1249 778 778412 1 21 22 123 Apr. 26, 1999 150 HODBB70 203918 Uni-ZAP XR 160 604 1604 173 413 1 7 8 27 Apr. 08, 1999 151 HOEBK60 203959 Uni-ZAP XR 1612218 1449 2216 1714 1714 414 1 39 40 43 Apr. 26, 1999 152 HOFNB74 203959pCMVSport 162 1036 1 1036 138 138 415 1 24 25 39 Apr. 26, 1999 2.0 153HOSDO75 PTA-181 Uni-ZAP XR 163 902 1 902 88 88 416 1 28 Jun. 07, 1999154 HOSEI81 203918 Uni-ZAP XR 164 897 1 897 203 203 417 1 22 23 83 Apr.08, 1999 155 HOUDE92 203918 Uni-ZAP XR 165 1284 1 1282 70 418 1 6 7 88Apr. 08, 1999 156 HOVBD85 203918 pSport1 166 1129 1 1129 252 252 419 119 20 26 Apr. 08, 1999 157 HPCAB41 203918 Uni-ZAP XR 167 2587 1 2587 184184 420 1 25 Apr. 08, 1999 158 HPEAD23 203959 Uni-ZAP XR 168 582 1 582188 188 421 1 13 14 93 Apr. 26, 1999 159 HPFCI36 PTA-181 Uni-ZAP XR 169879 1 879 94 94 422 1 17 18 19 Jun. 07, 1999 160 HPFDI37 PTA-181 Uni-ZAPXR 170 352 1 352 38 38 423 1 17 Jun. 07, 1999 161 HPIAA80 203959 Uni-ZAPXR 171 919 312 919 314 424 1 13 14 37 Apr. 26, 1999 162 HPJCW58 203918Uni-ZAP XR 172 1165 1 1165 177 177 425 1 19 20 28 Apr. 08, 1999 163HPMFH77 203918 Uni-ZAP XR 173 1891 1 1891 251 426 1 11 12 35 Apr. 08,1999 164 HPQCB83 203918 Lambda ZAP 174 2267 1 2267 85 85 427 1 30 31 34Apr. 08, 1999 II 165 HPRBH85 203959 Uni-ZAP XR 175 1673 558 1648 684 684428 1 18 19 134 Apr. 26, 1999 166 HPRCD35 PTA-181 Uni-ZAP XR 176 709 1689 265 429 1 16 17 35 Jun. 07, 1999 167 HPTRM02 203959 pBluescript 1771760 658 1680 885 885 430 1 16 17 80 Apr. 26, 1999 168 HRADA42 203959pCMVSport 178 1135 1 1135 122 431 1 24 25 44 Apr. 26, 1999 3.0 169HRADF49 PTA-181 pCMVSport 179 2704 1 2684 169 169 432 1 39 40 253 Jun.07, 1999 3.0 170 HRADN25 203959 pCMVSport 180 1225 17 1206 198 198 433 117 18 65 Apr. 26, 1999 3.0 171 HRDDQ39 203959 Uni-ZAP XR 181 776 1 773215 434 1 17 18 46 Apr. 26, 1999 172 HRDER22 203959 Uni-ZAP XR 182 543 1543 32 435 1 9 Apr. 26, 1999 173 HRDEX93 203959 Uni-ZAP XR 183 1681 7111638 649 649 436 1 20 21 72 Apr. 26, 1999 174 HRDFK37 203959 Uni-ZAP XR184 728 1 726 120 120 437 1 10 Apr. 26, 1999 175 HRTAP63 203979pBluescript 185 2576 891 2576 959 959 438 1 28 29 42 Apr. 29, 1999 SK−176 HSAVA08 203918 Uni-ZAP XR 186 1061 1 1061 66 439 1 17 18 26 Apr. 08,1999 177 HSAVW42 203959 Uni-ZAP XR 187 595 1 595 129 129 440 1 16 17 22Apr. 26, 1999 178 HSAYC41 203959 Uni-ZAP XR 188 214 1 214 106 106 441 116 17 36 Apr. 26, 1999 179 HSDZM54 203959 pBluescript 189 554 1 554 445445 442 1 15 16 36 Apr. 26, 1999 180 HSHBF76 203959 Uni-ZAP XR 190 12731 1213 129 443 1 7 8 10 Apr. 26, 1999 181 HSIFG47 203959 Uni-ZAP XR 191882 1 882 304 304 444 1 13 Apr. 26, 1999 182 HSJBY32 203918 Uni-ZAP XR192 1648 1 1648 257 257 445 1 19 20 91 Apr. 08, 1999 183 HSKDR27 203918Uni-ZAP XR 193 762 1 762 473 446 1 11 12 27 Apr. 08, 1999 184 HSNAP85203959 Uni-ZAP XR 194 1286 735 1286 941 447 1 4 Apr. 26, 1999 185HSNBM34 203959 Uni-ZAP XR 195 2186 1391 1765 1508 448 1 14 15 62 Apr.26, 1999 186 HSQDO85 PTA-181 Uni-ZAP XR 196 1210 1 1210 133 133 449 1 11Jun. 07, 1999 187 HSRBE06 PTA-791 Uni-ZAP XR 197 1633 13 1633 128 450 121 Sep. 27, 1999 188 HSSDI26 203918 Uni-ZAP XR 198 1406 1 1406 253 253451 1 21 Apr. 08, 1999 189 HSSEA64 PTA-181 Uni-ZAP XR 199 1282 1 1274 5858 452 1 16 17 62 Jun. 07, 1999 190 HSSEF77 203959 Uni-ZAP XR 200 1053 11053 184 453 1 25 26 60 Apr. 26, 1999 191 HSSFE38 203959 Uni-ZAP XR 2011238 85 1133 264 454 1 19 20 125 Apr. 26, 1999 192 HSXCP38 PTA-795Uni-ZAP XR 202 2206 1 2206 211 455 1 14 Sep. 27, 1999 193 HT1SC27 203959Uni-ZAP XR 203 1198 1 1198 366 366 456 1 19 20 27 Apr. 26, 1999 194HT4FV41 PTA-181 Uni-ZAP XR 204 1764 1 1764 39 457 1 16 17 137 Jun. 07,1999 195 HT5GR59 203959 Uni-ZAP XR 205 1743 1 1743 135 135 458 1 23 2431 Apr. 26, 1999 196 HTEAG62 203959 Uni-ZAP XR 206 2221 57 2221 10171017 459 1 20 21 22 Apr. 26, 1999 197 HTEEW69 203959 Uni-ZAP XR 207 1282110 1263 182 182 460 1 30 31 323 Apr. 26, 1999 198 HTEGS07 203959Uni-ZAP XR 208 806 1 806 493 461 1 20 21 37 Apr. 26, 1999 199 HTEGS11PTA-181 Uni-ZAP XR 209 981 1 981 173 462 1 7 Jun. 07, 1999 200 HTEHU59203959 Uni-ZAP XR 210 1523 1 1504 170 170 463 1 19 20 34 Apr. 26, 1999201 HTEJD29 203959 Uni-ZAP XR 211 1324 1 1324 101 101 464 1 23 Apr. 26,1999 202 HTEKM46 PTA-181 Uni-ZAP XR 212 2116 1 2116 171 171 465 1 24 2538 Jun. 07, 1999 203 HTENR63 PTA-792 Uni-ZAP XR 213 1591 1 1591 132 132466 1 20 21 56 Sep. 27, 1999 204 HTGGM44 203959 Uni-ZAP XR 214 3016 12761 179 179 467 1 18 19 84 Apr. 26, 1999 205 HTHBZ06 203959 Uni-ZAP XR215 623 193 619 318 318 468 1 1 Apr. 26, 1999 206 HTLAP64 203918 Uni-ZAPXR 216 1092 1 1092 173 173 469 1 19 20 20 Apr. 08, 1999 207 HTLBT80203959 Uni-ZAP XR 217 2101 817 1881 912 912 470 1 27 28 129 Apr. 26,1999 208 HTLDU78 203918 Uni-ZAP XR 218 1318 1 1318 219 219 471 1 8 Apr.08, 1999 209 HTLEM16 203959 Uni-ZAP XR 219 1915 1158 1755 1220 1220 4721 27 28 69 Apr. 26, 1999 210 HTLFA13 203918 Uni-ZAP XR 220 1160 1 1160209 473 1 8 9 31 Apr. 08, 1999 211 HTLGI89 203959 Uni-ZAP XR 221 23771205 2377 1802 1802 474 1 16 17 37 Apr. 26, 1999 212 HTLIF11 203959Uni-ZAP XR 222 1968 860 1968 933 933 475 1 33 34 38 Apr. 26, 1999 213HTNBK13 203959 pBluescript 223 1160 295 1148 534 534 476 1 16 17 21 Apr.26, 1999 SK− 214 HTOAM11 203918 Uni-ZAP XR 224 1200 1 1200 89 89 477 124 25 34 Apr. 08, 1999 215 HTODH83 203918 Uni-ZAP XR 225 1981 1 1981 103103 478 1 21 22 32 Apr. 08, 1999 216 HTPCO75 PTA-181 Uni-ZAP XR 226 14671 1467 73 479 1 23 24 40 Jun. 07, 1999 217 HTSFJ32 203918 pBluescript227 1257 517 1257 93 93 480 1 18 Apr. 08, 1999 218 HTTCB60 PTA-181Uni-ZAP XR 228 1504 1 1504 84 84 481 1 17 18 266 Jun. 07, 1999 219HTTEE41 203959 Uni-ZAP XR 229 1973 864 1968 1171 482 1 8 Apr. 26, 1999220 HTTEZ02 203918 Uni-ZAP XR 230 1880 1 1880 250 250 483 1 21 22 28Apr. 08, 1999 221 HTWEH94 203918 pSport1 231 1361 1 1361 66 66 484 1 4344 81 Arp. 08, 1999 222 HTXDC77 203979 Uni-ZAP XR 232 1441 159 1400 6565 485 1 18 19 151 Apr. 29, 1999 223 HTXDG92 203959 Uni-ZAP XR 233 11621 1162 216 486 1 24 25 66 Apr. 26, 1999 224 HTXET11 203918 Uni-ZAP XR234 989 1 989 178 178 487 1 22 23 29 Apr. 08, 1999 225 HTXFA72 PTA-181Uni-ZAP XR 235 1861 1 1861 192 192 488 1 17 18 29 Jun. 07, 1999 226HTXJY08 203959 Uni-ZAP XR 236 1187 12 1187 108 108 489 1 16 Apr. 26,1999 227 HTXMZ07 203959 Uni-ZAP XR 237 1652 189 1640 319 319 490 1 22 2337 Apr. 26, 1999 228 HUKBT67 203959 Lambda ZAP 238 2069 74 2052 273 4911 21 22 39 Apr. 26, 1999 II 229 HUKDF20 203918 Lambda ZAP 239 1105 11105 214 214 492 1 20 21 33 Apr. 08, 1999 II 230 HUSCJ14 PTA- Lambda ZAP240 3342 1 3342 74 74 493 1 30 31 196 1838 II May 09, 2000 231 HUSGL67203918 pSport1 241 1008 65 1008 350 350 494 1 21 22 47 Apr. 08, 1999 232HUSGU40 203959 pSport1 242 1054 1 1054 500 495 1 20 21 46 Apr. 26, 1999233 HUSIR18 203959 pSport1 243 876 1 876 83 83 496 1 16 17 22 Apr. 26,1999 234 HUVDJ48 203918 Uni-ZAP XR 244 1827 1 1827 196 196 497 1 5 Apr.08, 1999 235 HWDAC26 203959 pCMVSport 245 1958 1 1958 242 242 498 1 2526 35 Apr. 26, 1999 3.0 236 HWDAJ01 203959 pCMVSport 246 781 1 781 288288 499 1 24 Apr. 26, 1999 3.0 237 HBDAB91 203917 pSport1 247 1007 3201007 671 671 500 1 19 20 29 Apr. 08, 1999 237 HBDAB91 203917 pSport1 255687 1 687 351 351 508 1 19 20 29 Apr. 08, 1999 238 HILCA24 203960pBluescript 248 1982 153 1982 191 191 501 1 29 30 327 Apr. 26, 1999 SK−238 HILCA24 203960 pBluescript 256 1980 151 1976 189 189 509 1 29 30 327Apr. 26, 1999 SK− 239 HYABC84 203959 pCMVSport 249 1478 833 1306 10801080 502 1 28 29 62 Apr. 26, 1999 3.0 239 HYABC84 203959 pCMVSport 2571338 768 1238 1015 1015 510 1 28 29 62 Apr. 26, 1999 3.0 240 HE2CA60203960 Uni-ZAP XR 250 3034 1679 3034 1731 1731 503 1 7 Apr. 26, 1999 240HE2CA60 203960 Uni-ZAP XR 258 1663 308 1663 360 360 511 1 7 Apr. 26,1999 241 HPQAX38 203979 Lambda ZAP 251 1158 41 1158 295 504 1 10 11 16Apr. 29, 1999 II 241 HPQAX38 203979 Lambda ZAP 259 1157 41 1157 295 5121 10 11 16 Apr. 29, 1999 II 242 HE8FD92 203979 Uni-ZAP XR 252 3977 19863960 2141 2141 505 1 25 26 43 Apr. 29, 1999 242 HE8FD92 203979 Uni-ZAPXR 260 1995 1 1978 157 157 513 1 25 26 43 Apr. 29, 1999 242 HE8FD92203979 Uni-ZAP XR 261 4102 2114 4085 2268 2268 514 1 25 26 43 Apr. 29,1999 242 HE8FD92 203979 Uni-ZAP XR 262 4907 2918 4890 2 515 1 1 2 471Apr. 29, 1999 242 HE8FD92 203979 Uni-ZAP XR 263 2908 918 2891 1074 1074516 1 25 26 43 Apr. 29, 1999Table 1B (Comprised of Tables 1B.1 and 1B.2)

The first column in Table 1B.1 and Table 1B.2 provides the gene numberin the application corresponding to the clone identifier. The secondcolumn in Table 1B. 1 and Table 1B.2 provides a unique “Clone ID:” forthe cDNA clone related to each contig sequence disclosed in Table 1B. 1and Table 1B.2. This clone ID references the cDNA clone which containsat least the 5′ most sequence of the assembled contig and at least aportion of SEQ ID NO:X as determined by directly sequencing thereferenced clone. The referenced clone may have more sequence thandescribed in the sequence listing or the clone may have less. In thevast majority of cases, however, the clone is believed to encode afull-length polypeptide. In the case where a clone is not full-length, afull-length cDNA can be obtained by methods described elsewhere herein.The third column in Table 1B.1 and Table 1B.2 provides a unique “ContigID” identification for each contig sequence. The fourth column in Table1B.1 and Table 1B.2 provides the “SEQ ID NO:” identifier for each of thecontig polynucleotide sequences disclosed in Table 1B.

Table 1B.1

The fifth column in Table 1B. 1, “ORF (From-To)”, provides the location(i.e., nucleotide position numbers) within the polynucleotide sequence“SEQ ID NO:X” that delineate the preferred open reading frame (ORF)shown in the sequence listing and referenced in Table 1B.1, column 6, asSEQ ID NO:Y. Where the nucleotide position number “To” is lower than thenucleotide position number “From”, the preferred ORF is the reversecomplement of the referenced polynucleotide sequence. The sixth columnin Table 1B.1 provides the corresponding SEQ ID NO:Y for the polypeptidesequence encoded by the preferred ORF delineated in column 5. In oneembodiment, the invention provides an amino acid sequence comprising, oralternatively consisting of, a polypeptide encoded by the portion of SEQID NO:X delineated by “ORF (From-To)”. Also provided are polynucleotidesencoding such amino acid sequences and the complementary strand thereto.Column 7 in Table 1B.1 lists residues comprising epitopes contained inthe polypeptides encoded by the preferred ORF (SEQ ID NO:Y), aspredicted using the algorithm of Jameson and Wolf, (1988) Comp. Appl.Biosci. 4:181-186. The Jameson-Wolf antigenic analysis was performedusing the computer program PROTEAN (Version 3.11 for the PowerMacIntosh, DNASTAR, Inc., 1228 South Park Street Madison, Wis.). Inspecific embodiments, polypeptides of the invention comprise, oralternatively consist of, at least one, two, three, four, five or moreof the predicted epitopes as described in Table 1B. It will beappreciated that depending on the analytical criteria used to predictantigenic determinants, the exact address of the determinant may varyslightly.

Column 8 in Table 1B.1 provides a chromosomal map location for certainpolynucleotides of the invention. Chromosomal location was determined byfinding exact matches to EST and cDNA sequences contained in the NCBI(National Center for Biotechnology Information) UniGene database. Eachsequence in the UniGene database is assigned to a “cluster”; all of theESTs, cDNAs, and STSs in a cluster are believed to be derived from asingle gene. Chromosomal mapping data is often available for one or moresequence(s) in a UniGene cluster; this data (if consistent) is thenapplied to the cluster as a whole. Thus, it is possible to infer thechromosomal location of a new polynucleotide sequence by determining itsidentity with a mapped UniGene cluster.

A modified version of the computer program BLASTN (Altshul, et al., J.Mol. Biol. 215:403-410 (1990), and Gish, and States, Nat. Genet.3:266-272) (1993) was used to search the UniGene database for EST orcDNA sequences that contain exact or near-exact matches to apolynucleotide sequence of the invention (the ‘Query’). A sequence fromthe UniGene database (the ‘Subject’) was said to be an exact match if itcontained a segment of 50 nucleotides in length such that 48 of thosenucleotides were in the same order as found in the Query sequence. Ifall of the matches that met this criteria were in the same UniGenecluster, and mapping data was available for this cluster, it isindicated in Table 1B under the heading “Cytologic Band”. Where acluster bad been further localized to a distinct cytologic band, thatband is disclosed; where no banding information was available, but thegene had been localized to a single chromosome, the chromosome isdisclosed.

Once a presumptive chromosomal location was determined for apolynucleotide of the invention, an associated disease locus wasidentified by comparison with a database of diseases which have beenexperimentally associated with genetic loci. The database used was theMorbid Map, derived from OMIM™ and National Center for BiotechnologyInformation, National Library of Medicine (Bethesda, Md.) 2000;. If theputative chromosomal location of a polynucleotide of the invention(Query sequence) was associated with a disease in the Morbid Mapdatabase, an OMIM reference identification number was noted in column 9,Table 1B.1, labelled “OMIM Disease Reference(s). Table 5 is a key to theOMIM reference identification numbers (column 1), and provides adescription of the associated disease in Column 2.

Table 1B.2

Column 5, in Table 1B.2, provides an expression profile and librarycode:count for each of the contig sequences (SEQ ID NO:X) disclosed inTable 1B, which can routinely be combined with the information providedin Table 4 and used to determine the tissues, cells, and/or cell linelibraries which predominantly express the polynucleotides of theinvention. The first number in Table 1B.2, column 5 (preceding thecolon), represents the tissue/cell source identifier code correspondingto the code and description provided in Table 4. The second number incolumn 5 (following the colon) represents the number of times a sequencecorresponding to the reference polynucleotide sequence was identified inthe corresponding tissue/cell source. Those tissue/cell sourceidentifier codes in which the first two letters are “AR” designateinformation generated using DNA array technology. Utilizing thistechnology, cDNAs were amplified by PCR and then transferred, induplicate, onto the array. Gene expression was assayed throughhybridization of first strand cDNA probes to the DNA array. cDNA probeswere generated from total RNA extracted from a variety of differenttissues and cell lines. Probe synthesis was performed in the presence of³³P dCTP, using oligo (dT) to prime reverse transcription. Afterhybridization, high stringency washing conditions were employed toremove non-specific hybrids from the array. The remaining signal,emanating from each gene target, was measured using a Phosphorimager.Gene expression was reported as Phosphor Stimulating Luminescence (PSL)which reflects the level of phosphor signal generated from the probehybridized to each of the gene targets represented on the array. A localbackground signal subtraction was performed before the total signalgenerated from each array was used to normalize gene expression betweenthe different hybridizations. The value presented after “[array code]:”represents the mean of the duplicate values, following backgroundsubtraction and probe normalization. One of skill in the art couldroutinely use this information to identify normal and/or diseasedtissue(s) which show a predominant expression pattern of thecorresponding polynucleotide of the invention or to identifypolynucleotides which show predominant and/or specific tissue and/orcell expression. TABLE 1B.1 AA SEQ SEQ ID ID OMIM Gene cDNA Contig NO:ORF NO: Cytologic Disease No: Clone ID ID: X (From-To) Y PredictedEpitopes Band Reference(s): 1 H6BSF56 762968 11  83-508 264 Asn-131 toMet-140. 2 H6EDM64 841331 12 1448-1468 265 11q13 102200, 106100, 131100,131100, 131100, 133780, 147050, 153700, 161015, 164009, 168461, 168461,168461, 180721, 180840, 191181, 193235, 209901, 232600, 259700, 259770,600045, 600319, 600528, 601884 3 H6EEC72 889401 13 263-319 266 19q13.4134790, 191044, 600040, 600138 4 H6EEU40 757048 14 175-318 267 11q12.1106100, 147050, 259700, 259770, 600045, 601884 5 HACAB68 584773 15135-371 268 Leu-6 to Ser-12. 6 HACBJ56 847112 16 250-327 269 Arg-14 toIle-24. 7 HADMB15 847116 17 238-300 270 8 HAGFS57 847120 18 241-405 271Met-1 to Lys-6. 15q15.3 114240, 224120, 600839, 602099 9 HAGHN57 77328619 900-932 272 7q22-q32 126650, 126650, 154276, 173360, 173360, 180105,190900, 222800, 246900, 602136, 602136, 602136, 602447 10 HAJAA47 53467020 192-308 273 Leu-33 to Asp-38. 11 HAJAY92 845601 21  12-296 274 Lys-89to Glu-94. 12 HAJBV67 866415 22  605-1684 275 Arg-24 to Trp-44, 10q23.33157640, 174900, 236730, 600512 Leu-87 to Ser-93, Arg-119 to Trp-125,Pro-206 to Lys-211, Glu-280 to Trp-286. 13 HATCD80 826098 23 296-409 27614 HATEH20 836056 24  93-221 277 Val-23 to Glu-28. 15 HBAGD86 838799 25521-580 278 16 HBGBC29 691473 26 1016-1024 279 3q13.3 126451, 600882 17HBGNC72 892131 27 550-780 280 His-49 to His-57. 19p13.3 108725, 120700,133171, 136836, 145981, 147141, 164953, 188070, 600957, 601238, 601846,602216, 602477 18 HBHAA05 603174 28 110-286 281 19 HBHAA81 846465 29 28-639 282 3p21.32 116806, 168468, 182280, 600163 20 HBIAC29 831751 301036-1125 283 1p35.3-p33 118210, 120260, 120550, 120570, 120575, 121800,130500, 133200, 138140, 171760, 171760, 178300, 185470, 230350, 246450,255800, 602771 21 HBJAB02 837309 31  84-188 284 Arg-24 to Asp-31. 17q23106180, 138700, 139250, 150200, 154275, 176960, 249000, 253250 22HBJAC40 841235 32 329-370 285 16p13.3 141750, 141800, 141800, 141800,141800, 141850, 141850, 141850, 141850, 141850, 156850, 186580, 191092,600140, 600273, 601313, 601785 23 HBJCR46 815649 33  589-2787 286 Met-1to Ala-8, 15q12 103581, 146150, 182279, 203200, 203200, Phe-42 toAsp-57, 227220, 601623, 601800, 601889, 602117 Tyr-105 to Thr-110,His-121 to Cys-127, Asp-154 to Lys-181, Arg-186 to Pro-210, Ala-233 toAsp-252, Ser-296 to Ser-306, Pro-313 to Ser-320, Gln-331 to Gly-346,Ser-355 to Thr-360, Cys-386 to Phe-395, Ser-400 to Glu-425, Thr-440 toThr-446, Pro-449 to Cys-466, Glu-470 to Thr-509, Ser-512 to Asp-533,Ala-544 to Arg-550, Arg-562 to Glu-571, Lys-587 to Thr-594, Asp-713 toGlu-733. 24 HBJDW56 520401 34 121-147 287 25 HBJEL16 847030 35 115-225288 1q23.1-q23.2 107300, 131210, 136132, 145001, 173610, 249270, 60165226 HBJKD16 853358 36  78-173 289 2p14 203800 27 HBMBM96 561935 37170-184 290 28 HBMTM11 589515 38 125-220 291 29 HBMUH74 866160 39344-430 292 12p11.22 112410, 135700, 168470, 200990 30 HBQAB79 810542 40190-225 293 4q31.1 189800, 600983 31 HBSAK32 856387 41 447-590 294 20p13192340, 234200 32 HBXCX15 637542 42 72-77 295 33 HCDCY76 837972 43860-967 296 Pro-20 to Phe-25. 11q14-q21 133780, 203100, 203100, 24500034 HCDDL48 839743 44 333-455 297 Thr-26 to Tyr-38. 35 HCE1G78 761204 45 77-841 298 Asp-20 to Thr-26, 22q11.2-q13.2 123620, 138720, 145410,188826, 231950, Leu-30 to Gly-38, 239500, 275350, 600850 Asp-63 toPhe-72, Gly-160 to Trp-175, Gly-189 to Ser-197, Thr-214 to Val-221. 36HCE5F78 838101 46 566-664 299 Tyr-21 to Lys-30. 37 HCEDR26 771144 47177-344 300 38 HCEEQ25 531784 48 111-182 301 Met-14 to Asn-19. 39HCEEU18 688041 49 209-340 302 40 HCEGG08 844506 50 1114-1197 303 41HCFLN88 610000 51 101-178 304 7q11.23 116860, 129900, 233700, 600079 42HCHAB84 834326 52 304-747 305 Asn-47 to Leu-52, Tyr-134 to Trp-143. 43HCMSX51 788643 53 539-781 306 Leu-57 to Glu-66. 8p21 152760, 180100,185430, 602629 44 HCNCO11 775086 54 101-145 307 45 HCNSD29 862314 551145-1240 308 2q23.3 46 HCQBH72 637548 56  31-174 309 47 HCQCC96 84506657 782-919 310 48 HCUCF89 637986 58 189-278 311 Gly-14 to Asp-21. 49HCUCK44 790277 59 598-780 312 19q13.1 164731, 172400, 172400, 180901,180901, 221770, 248600, 600918, 602716 50 HCUDD64 835082 60 256-402 313Met-1 to Ser-6, 19p13.3 108725, 120700, 133171, 136836, 145981, Gln-32to Asn-39. 147141, 164953, 188070, 600957, 601238, 601846, 602216,602477 51 HCWAE64 535893 61 410-427 314 52 HDPDI72 897277 62  23-385 315Arg-63 to Phe-72, Ile-114 to Phe-120. 53 HDPGE24 801947 63 173-394 31654 HDPIU94 813352 64 208-279 317 8q21.1 138300, 240400, 602629 55HDPIY31 886159 65 268-375 318 20q13.33 56 HDPOC24 777493 66 418-819 319Pro-36 to Cys42, 9q34.12 Pro-44 to Cys-54, Arg-100 to Gly-105. 57HDPOL37 745377 67 189-377 320 Met-1 to Arg-8, Gly-29 to Glu-36. 58HDPOO76 838594 68 109-159 321 59 HDPPQ30 684292 69 220-336 322 60HDQHM36 852328 70 129-275 323 61 HE2CM39 553651 71 10-51 324 62 HE2PO93771655 72 770-898 325 3p21.3 116806, 120120, 120120, 120120, 120436,120436, 120436, 138320, 168468, 182280, 600163 63 HE6FU11 827236 73145-825 326 64 HE6FV29 588454 74 210-311 327 65 HE9EA10 827796 75212-448 328 Arg-6 to Trp-11. 66 HEBCY54 600355 76 172-528 329 Arg-18 toLys-26, 8p22-p21 148370, 152760, 180100, 185430, 238600, Gly-35 toAla-42, 238600, 238600, 238600, 600143, 601385, Gln-61 to Gly-67. 60262967 HEBDF77 692347 77 681-791 330 68 HEBDQ91 840288 78 1211-1336 331 69HEBFR46 847064 79 200-289 332 Met-1 to Thr-6. 70 HEBGE07 798096 80106-234 333 71 HEGAU15 834379 81  59-163 334 72 HEQBF89 786205 82306-458 335 Glu-17 to Gly-22, Arg-29 to Phe-36. 73 HFCEI04 692438 83136-264 336 Asn-21 to Gly-28. 74 HFEAY59 658685 84 154-276 337 Arg-2 toLys-8, Arg-22 to Lys-31. 75 HFIJA68 847074 85 283-414 338 76 HFKEU12634006 86  6-173 339 Pro-18 to Thr-55. 77 HFPCZ55 840840 87 676-810 34011p15 108985, 186921, 602092 78 HFTBM38 638338 88 577-669 341 79 HFTDH56862021 89 67-99 342 4q11 103600, 103600, 103600, 104150, 104150, 104500,170650 80 HFVHW43 570948 90  92-211 343 81 HGBHP91 693011 91  50-208 34482 HHEAK45 765278 92 813-824 345 6p21.33 248611 83 HHEGS55 858372 93159-269 346 84 HHEOW19 886174 94 183-377 347 Ala-41 to Pro-57. 1q42106150, 106150, 145260, 173870, 173870, 600759, 600996, 601744, 60197585 HHFFL34 753230 95  42-713 348 Asn-146 to Arg-157, Leu-168 to Asn-183,Gln-189 to Asn-199, Gln-206 to Ser-217. 86 HHFFS40 824059 96  37-180 3495p14.1 123000 87 HHGCS78 634605 97 290-364 350 17q11.1 182138, 600881,601954 88 HHGDT26 658692 98 181-207 351 89 HHPFU28 824573 99 156-239 352Ser-12 to Tyr-17. 4q12 103600, 103600, 103600, 104150, 104150, 104500,164920, 164920, 164920, 170650, 600900 90 HHSBI06 639097 100 690-707 35391 HHSBI65 801910 101  62-229 354 Ala-16 to Val-35. 8q24.3 188450,188450, 188450 92 HHSDI53 862028 102 221-295 355 93 HISAT67 843549 1031239-1409 356 2p23.3 176830, 176830, 182601, 229800, 602134 94 HJBCU75638329 104 61-78 357 95 HJMAA03 824062 105 527-556 358 96 HJMAV41 862029106 207-290 359 19p12 601843 97 HJMAY90 793678 107 2492-2596 360 5q35.398 HJPBE39 801960 108 170-226 361 11q22.1 133780, 602574, 602574 99HJPCH08 840365 109 374-727 362 Glu-3 to Phe-9, Gln-17 to Leu-50. 100HKGBF25 738797 110 261-371 363 101 HKIXC44 716213 111 572-682 364 102HKTAB41 695732 112 172-204 365 103 HLDBG17 855953 113 184-309 366 Leu-29to His-34. 104 HLDQU79 740755 114  99-1142 367 Leu-68 to Lys-74, Tyr-109to Lys-115, Gln-200 to Val-205, Lys-207 to Lys-214, Glu-237 to Ile-244,Ala-271 to Thr-279, Ser-317 to Ser-329, Gln-342 to Gly-348. HLDQU79837599 253  75-1121 506 105 HLDRT09 830544 115 522-719 368 Ser-18 toSer-30. 2q36 120070, 120131, 120131, 138030, 147545, 259900, 262000 106HLHAP05 638476 116 45-89 369 Gln-4 to Leu-14. 107 HLHCS23 560663 117 25-129 370 108 HLIBO72 883431 118 167-550 371 109 HLICE88 840321 119708-716 372 4q28 107250, 134820, 134820, 134820, 134830, 134850, 134850,181600, 189800, 266300 110 HLICO10 658740 120 441-659 373 Pro-30 toAsn-42, 20q13.13 602025 Ser-49 to Val-55, Ser-67 to Ser-72. 111 HLJBS28658742 121 359-412 374 Xq26.1-q27.2 300123, 301201, 301590, 301845,301900, 304340, 306900, 307150, 307700, 308000, 308000, 309000, 310490,313850 112 HLMJB64 658699 122  12-161 375 Ser-6 to Gly-11.20q11.1-q11.23 113 HLWAV47 897769 123 200-298 376 1q41 145260, 276901,600332, 600759, 601744, 601975 114 HLYDF73 566869 124 363-434 377 115HLYGE16 651339 125 406-627 378 Arg-23 to Trp-42, 7q32.2 180105, 222800Val-52 to Pro-61. 116 HLYGY91 658703 126 211-339 379 117 HMCFH60 654853127 211-357 380 6pter-p24.1 118 HMDAB29 584789 128  97-177 381 119HMDAD44 566854 129 135-161 382 120 HMEDI90 840077 130 622-675 383 Ser-7to Thr-13. 121 HMIAK10 562774 131 195-290 384 122 HMIBF07 603528 132229-249 385 123 HMICI80 827318 133 1149-1247 386 Gln-13 to Tyr-20. 124HMJAK70 610099 134 273-305 387 125 HMTAB77 847411 135 769-915 388 Gly-3to Thr-8. 1p13.2 102770, 164790, 601414, 601691, 601691, 601691, 601691,601718, 602094 126 HMUAE26 747403 136 710-802 389 Ser-25 to Arg-30.3q21.2 106165, 117700, 117700, 150210, 169600, 180380, 180380, 180380,203500, 232050, 276902, 600882, 601199, 601199, 601199, 601471, 601682127 HMUAN45 833072 137 239-922 390 Pro-33 to Gly-45, 11q13.5 133780,266150, 276903, 276903, 276903 Cys-121 to Gly-131, Ala-155 to His-166,Gly-180 to Gln-185. 128 HMVBC31 825598 138 1437-1559 391 Ser-33 toTyr-39. 1p36.21 120550, 120570, 120575, 153454, 256700 129 HMWBL03822861 139  137-1327 392 Met-1 to Leu-11, Val-13 to Lys-19, Thr-30 toAsp-39, Thr-49 to Gly-68, Ala-78 to Gly-111, Pro-140 to Thr-163, Ser-169to Ser-185, Glu-197 to Lys-204, Lys-210 to Asp-215, Glu-220 to Ser-231,Ser-255 to Leu-266, Thr-269 to Asp-288, Cys-300 to Val-309, Phe-331 toCys-339, Ser-362 to Ile-373. 130 HMWCG28 847413 140  78-200 393 12p13.3103950, 193100, 193400, 200990, 601458 131 HNECW49 639117 141 316-489394 Cys-21 to Trp-26, Val-37 to Ser-53. 132 HNFCY57 877653 142  317-2206395 Leu-15 to Leu-25, 1q44 601975 Arg-47 to His-53, Glu-130 to Asn-138,Pro-140 to Ser-148, Asn-157 to Lys-163, Asn-178 to Lys-187, Pro-281 toArg-292, Leu-341 to Leu-346, Lys-471 to Cys-477, Arg-513 to Gly-521,Gly-570 to Gly-575, Leu-614 to Glu-620. 133 HNFGR08 825417 143 314-445396 134 HNGAK51 603910 144 248-346 397 135 HNGAM58 688114 145  68-412398 Trp-31 to Arg-39, Ala-50 to Trp-57, Lys-83 to Leu-93, Pro-103 toGly-113. 136 HNGDX18 1145071 146 237-965 399 Ser-21 to Ser-39, Gln-45 toGln-61, Cys-124 to Ser-139. HNGDX18 866177 254 231-629 507 Ser-21 toSer-39, Gln-45 to Gln-61, Cys-124 to Gly-130. 137 HNGEQ75 535723 14730-98 400 12q24.12 160781, 181405 138 HNGFR54 695748 148  73-231 401Trp-6 to Tyr-11. 139 HNGGA68 638116 149 184-282 402 Ala-8 to Gly-20. 140HNGHZ69 899289 150 25-54 403 141 HNGKT41 836061 151 415-552 404 142HNGMW45 838613 152 452-583 405 143 HNGNO53 836063 153 467-571 406 144HNGPJ25 834942 154 544-621 407 145 HNHFE71 834487 155 598-663 408 146HNHGK22 597451 156 239-433 409 147 HNHKS19 778392 157 192-317 410 Pro-23to Gln-34. 148 HNHKV56 800877 158 294-494 411 149 HOACG07 792928 159 778-1149 412 Pro-32 to Ser-42, 20p13 192340, 234200 Cys-51 to Gly-83,Gly-87 to Ser-93. 150 HODBB70 520196 160 173-256 413 151 HOEBK60 789396161 1714-1845 414 Lys-5 to Thr-10, Gln-36 to Gly-43. 152 HOFNB74 762821162 138-257 415 Ser-30 to Ser-36. 12q12-12q14.3 181430, 600194, 600231,600808, 601284, 601769, 601769, 602116 153 HOSDO75 862049 163  88-174416 Phe-2 to Ser-8, 11q13.4 133780, 266150 Phe-21 to Ser-26. 154 HOSEI81562778 164 203-454 417 Lys-70 to Asn-76. 12q12-q13 107777, 123940,139350, 139350, 148040, 148041, 148043, 148070, 231550, 600194, 600231,600536, 600808, 600956, 601284, 601769, 601769, 601928, 602116, 602153155 HOUDE92 580866 165  70-336 418 Pro-22 to His-31, Ser-80 to Gln-88.156 HOVBD85 827362 166 252-332 419 157 HPCAB41 758003 167 184-261 420158 HPEAD23 773409 168 188-469 421 Ala-54 to Lys-59. 159 HPFCI36 855966169  94-153 422 10q23.31 157640, 174900, 236730, 600512 160 HPFDI37862056 170 38-91 423 22q11.21 123620, 151410, 600850 161 HPIAA80 829972171 314-427 424 162 HPJCW58 612866 172 177-263 425 Leu-16 to Gly-21. 163HPMFH77 702014 173 251-358 426 Pro-29 to Cys-35. 164 HPQCB83 740761 174 85-189 427 165 HPRBH85 695752 175  684-1088 428 Glu-121 to Leu-126.3q21.1 106165, 117700, 117700, 150210, 169600, 180380, 180380, 180380,203500, 232050, 276902, 600882, 601199, 601199, 601199, 601471, 601682166 HPRCD35 853551 176 265-372 429 Asp-16 to Gln-27. 167 HPTRM02 812879177  885-1127 430 His-48 to Ser-61, 7 Ala-66 to Val-72. 168 HRADA42827302 178 122-256 431 Xq22-24 300046, 300088, 300123, 300300, 300300,301201, 301500, 301835, 301845, 303630, 303630, 303631, 304500, 304700,304700, 304700, 307150, 309300, 309605, 310490, 311850, 312080, 312080169 HRADF49 866481 179 169-930 432 Pro-85 to Asp-99, 2q36.1 120070,120131, 120131, 138030, 259900 Arg-163 to Arg-170, Gln-183 to Thr-189,Pro-201 to Ser-209, Ser-216 to Gly-222. 170 HRADN25 800628 180 198-395433 Gly-60 to Pro-65. 12q13 107777, 123940, 139350, 139350, 148040,148041, 148043, 148070, 231550, 600194, 600231, 600536, 600808, 600956,601284, 601769, 601769, 601928, 602116, 602153 171 HRDDQ39 840405 181215-355 434 Gly-27 to Pro-35. 172 HRDER22 688056 182 32-61 435 173HRDEX93 816046 183 649-867 436 1p34 130500, 133200, 138140, 168360,171760, 171760, 176100, 176100, 178300, 230000, 255800 174 HRDFK37840381 184 120-152 437 175 HRTAP63 780698 185  959-1087 438 Asn-2 toTrp-13. 2p23.3 176830, 176830, 182601, 229800, 602134 176 HSAVA08 580870186  66-146 439 Thr-15 to Gln-22. 177 HSAVW42 637660 187 129-197 4403p22.3 182280, 227646, 261510, 600163, 601154 178 HSAYC41 688057 188106-213 441 Lys-23 to Lys-36. 11q12.1 106100, 147050, 259700, 259770,600045, 601884 179 HSDZM54 637870 189 445-552 442 Lys-17 to Leu-23. 180HSHBF76 715838 190 129-161 443 181 HSIFG47 778378 191 304-345 444 182HSJBY32 702020 192 257-532 445 Pro-49 to Ala-69, 11p15.5 125852, 126452,126452, 141900, 141900, Pro-72 to His-77, 141900, 141900, 141900,141900, 142000, Pro-79 to Cys-89. 142000, 142200, 142250, 142270,176730, 176730, 176730, 190020, 191290, 192500, 192500, 194071, 194071,204500, 600856, 601680, 602631, 602631 183 HSKDR27 580874 193 473-556446 Pro-18 to Gly-26. 19p13.2 108725, 120700, 133171, 143890, 147670,147670, 147670, 151440, 164953, 231670, 600276, 600957, 601843 184HSNAP85 784054 194 941-955 447 185 HSNBM34 635131 195 1508-1696 448Ala-17 to Thr-26, 17p13-p11 100710, 138190, 254210, 271900, 600179,Gly-49 to Gln-62. 600977, 601202, 601777 186 HSQDO85 853393 196 133-168449 22q13.1 103050, 103050, 124030, 124030, 138981, 182380, 188826,190040, 190040, 190040 187 HSRBE06 871264 197 128-193 450 188 HSSDI26560722 198 253-318 451 189 HSSEA64 853395 199  58-246 452 190 HSSEF77658725 200 184-366 453 Arg-22 to Lys-27, 2p12 147200, 178640, 216900Leu-30 to Asn-39. 191 HSSFE38 742512 201 264-641 454 Glu-37 to Arg-42,Gly-108 to Cys-117. 192 HSXCP38 895392 202 211-255 455 193 HT1SC27630647 203 366-449 456 194 HT4FV41 853400 204  39-452 457 Ala-15 toGln-22, 19p13.3 108725, 120700, 133171, 136836, 145981, Gly-36 toGly-41, 147141, 164953, 188070, 600957, 601238, Arg-47 to Pro-63,601846, 602216, 602477 Pro-85 to His-98. 195 HT5GR59 801930 205 135-230458 8p21.3 602629 196 HTEAG62 812332 206 1017-1085 459 197 HTEEW69764835 207  182-1153 460 Asp-63 to Thr-70, Asn-77 to Ser-86, Thr-101 toArg-108, Pro-117 to Asn-123, Gly-194 to Trp-203. 198 HTEGS07 827700 208493-606 461 Pro-18 to Asn-27. 199 HTEGS11 862066 209 173-196 462 5p15.1123000 200 HTEHU59 840385 210 170-274 463 Ser-29 to Phe-34. 201 HTEJD29695798 211 101-172 464 202 HTEKM46 862069 212 171-287 465 203 HTENR63877952 213 132-302 466 Pro-22 to Lys-28. 4q24 157147, 248510 204 HTGGM44842856 214 179-433 467 3q23 106165, 110100, 117700, 117700, 150210,169600, 180380, 180380, 180380, 203500, 276902, 601199, 601199, 601199,601682 205 HTHBZ06 832477 215 318-323 468 12q24.31 181405 206 HTLAP64603913 216 173-235 469 Ile-8 to Asn-20. 11p15.5-p15.4 125852, 126452,126452, 130650, 141900, 141900, 141900, 141900, 141900, 141900, 142000,142000, 142200, 142250, 142270, 150000, 176730, 176730, 176730, 190020,191290, 192500, 192500, 194071, 194071, 204500, 257200, 257200, 600856,601680, 602631, 602631 207 HTLBT80 840045 217  912-1301 470 Ser-107 toSer-116. 20q11.21-q13.11 102700, 102700, 602025 208 HTLDU78 637702 218219-245 471 209 HTLEM16 779133 219 1220-1429 472 Arg-29 to Cys-43. 210HTLFA13 535937 220 209-304 473 211 HTLGI89 835069 221 1802-1915 474 212HTLIF11 843506 222  933-1049 475 Pro-4 to Gly-9. 213 HTNBK13 831967 223534-599 476 22q12 123620, 133450, 133450, 600850, 601669 214 HTOAM11664508 224  89-193 477 215 HTODH83 580884 225 103-201 478 216 HTPCO75853645 226  73-195 479 217 HTSFJ32 637720 227  93-149 480 Leu-12 toCys-18. 17p13.1 191170, 191170 218 HTTCB60 853401 228  84-884 481 Ser-83to Asp-88, Val-166 to Gly-181, Pro-193 to Ala-199, Glu-235 to Gln-250.219 HTTEE41 840950 229 1171-1197 482 12q15 181430, 600698, 600698,600698, 600698, 600808, 602116 220 HTTEZ02 702027 230 250-336 483 Arg-23to Leu-28. 7q34 180105, 222800, 274180 221 HTWEH94 561680 231  66-311484 222 HTXDC77 844258 232  65-520 485 223 HTXDG92 658730 233 216-416486 17q11.2 154275, 162200, 162200, 182138, 239100, 600881, 601954,602403 224 HTXET11 581521 234 178-267 487 225 HTXFA72 853410 235 192-281488 226 HTXJY08 637774 236 108-158 489 227 HTXMZ07 834881 237 319-432490 Pro-19 to Ser-28. 3p21.31 116806, 168468, 182280, 212138, 600163 228HUKBT67 844446 238 273-392 491 Ser-32 to Arg-39. 12q13.13 120140,120140, 120140, 120140, 120140, 120140, 120140, 126337, 600808, 601284,601769, 601769, 602116 229 HUKDF20 566823 239 214-315 492 230 HUSCJ14894699 240  74-661 493 Phe-166 to Arg-174, Ser-191 to Tyr-196. 231HUSGL67 792637 241 350-493 494 Met-1 to Tyr-8, 19q13.33 134790, 600040Gln-27 to Gln-38. 232 HUSGU40 684975 242 500-640 495 Arg-21 to Ser-27,Ile-36 to Asp-41. 233 HUSIR18 762858 243  83-151 496 6pter-p12.1 234HUVDJ48 564853 244 196-213 497 235 HWDAC26 821335 245 242-349 498Xq21.3-q22 300088, 300300, 300300, 301201, 301500, 301835, 303400,303630, 303630, 303631, 304500, 304700, 304700, 304700, 305450, 309300,309605, 311850, 312080, 312080 236 HWDAJ01 794016 246 288-362 499 Pro-17to Ser-24. 237 HBDAB91 864374 247 671-760 500 Lys-21 to Gln-29. HBDAB91789532 255 351-440 508 Lys-21 to Gln-29. 238 HILCA24 869856 248 191-1174 501 Gln-52 to Arg-57, 5p15.2 123000, 602568 Glu-74 to Leu-84,Val-104 to Asp-110, Gly-157 to Gly-163, Asn-185 to Ser-195, Arg-245 toAsp-250, Pro-302 to Pro-310, Thr-316 to Tyr-322. HILCA24 782450 256 189-1172 509 Gln-52 to Arg-57, Glu-74 to Leu-84, Val-104 to Asp-110,Gly-157 to Gly-163, Asn-185 to Ser-195, Arg-245 to Asp-250, Pro-302 toPro-310, Thr-316 to Tyr-322. 239 HYABC84 865064 249 1080-1268 502 Pro-3to Ala-8. 20q11.22 HYABC84 789854 257 1015-1203 510 Pro-3 to Ala-8. 240HE2CA60 888705 250 1731-1754 503 HE2CA60 770301 258 360-383 511 241HPQAX38 845752 251 295-345 504 HPQAX38 843592 259 295-345 512 242HE8FD92 901142 252 2141-2272 505 HE8FD92 888274 260 157-288 513 HE8FD92869847 261 2268-2399 514 HE8FD92 856544 262   2-1414 515 Asp-11 toTyr-16. HE8FD92 843825 263 1074-1205 516

TABLE 1B.2 Tissue Distribution Library Code: Count Gene No: cDNA CloneID Contig ID: SEQ ID NO: X ORF (From-To) (see Table 4 for Library Codes)1 H6BSF56 762968 11  83-508 AR313: 120, AR039: 99, AR299: 64, AR185: 57,AR089: 54, AR096: 51, AR277: 46, AR300: 43, AR316: 37, AR060: 29, AR218:28, AR240: 28, AR104: 25, AR219: 23, AR282: 23, AR055: 20, AR283: 12,L0599: 4, L0439: 3, L0777: 3, H0253: 2, H0615: 2, H0520: 2, L0754: 2,L0745: 2, L0759: 2, H0556: 1, H0657: 1, S0116: 1, H0450: 1, S0418: 1,S0046: 1, S0222: 1, H0492: 1, S0049: 1, H0570: 1, H0123: 1, H0050: 1,H0051: 1, S0036: 1, H0494: 1, L0805: 1, L0776: 1, S0126: 1, H0435: 1,H0670: 1, S0028: 1, L0747: 1, S0026: 1 and H0542: 1. 2 H6EDM64 841331 121448-1468 AR277: 22, AR060: 22, AR055: 21, AR283: 18, AR282: 18, AR104:16, AR185: 16, AR089: 16, AR299: 16, AR219: 14, AR240: 14, AR316: 13,AR096: 12, AR218: 12, AR039: 11, AR300: 11, AR313: 11, H0333: 6, H0556:5, H0255: 5, H0618: 4, L0783: 4, S0358: 3, H0549: 3, S0222: 3, H0318: 3,H0052: 3, H0553: 3, H0135: 3, L0769: 3, L3905: 3, H0547: 3, H0521: 3,H0555: 3, H0423: 3, H0716: 2, H0341: 2, H0402: 2, H0592: 2, H0253: 2,S0474: 2, H0620: 2, H0181: 2, H0617: 2, H0059: 2, L0761: 2, L0764: 2,L0809: 2, L5622: 2, H0520: 2, H0682: 2, S0330: 2, H0436: 2, L0751: 2,L0747: 2, L0750: 2, L0755: 2, S0436: 2, L0596: 2, L0601: 2, H0624: 1,H0686: 1, H0295: 1, T0049: 1, H0657: 1, H0656: 1, H0484: 1, H0483: 1,S0356: 1, S0442: 1, S0354: 1, S0360: 1, S0410: 1, H0729: 1, H0742: 1,S0045: 1, S0476: 1, H0619: 1, S0300: 1, L0717: 1, S0220: 1, H0370: 1,H0455: 1, H0586: 1, H0587: 1, H0559: 1, L0623: 1, T0082: 1, H0581: 1,H0183: 1, H0205: 1, H0327: 1, H0050: 1, H0687: 1, H0615: 1, T0006: 1,H0424: 1, H0213: 1, H0606: 1, H0166: 1, S0366: 1, H0090: 1, H0087: 1,H0264: 1, H0488: 1, H0413: 1, H0100: 1, H0625: 1, H0561: 1, H0130: 1,H0633: 1, H0647: 1, S0426: 1, H0529: 1, L0371: 1, L0796: 1, L0637: 1,L5566: 1, L0648: 1, L0364: 1, L0649: 1, L0774: 1, L0375: 1, L0378: 1,L0659: 1, L0636: 1, L5623: 1, L4501: 1, L0663: 1, H0693: 1, H0593: 1,S0126: 1, H0522: 1, S0027: 1, S0028: 1, L0740: 1, L0780: 1, L0758: 1,H0445: 1, S0011: 1, H0136: 1, S0196: 1 and H0352: 1. 3 H6EEC72 889401 13263-319 AR282: 2, AR039: 1, AR055: 1, S0444: 2, S0410: 2, H0559: 2,H0575: 2, H0618: 2, H0050: 2, H0521: 2, H0295: 1, H0650: 1, H0255: 1,S0418: 1, S0358: 1, S0376: 1, H0580: 1, S0045: 1, S0046: 1, H0550: 1,H0610: 1, H0497: 1, H0069: 1, H0635: 1, H0546: 1, H0086: 1, H0009: 1,H0059: 1, H0100: 1, H0429: 1, H0494: 1, L0766: 1, L0665: 1, H0519: 1,H0711: 1, S0152: 1, H0555: 1, L0743: 1, L0748: 1, L0747: 1, L0759: 1,S0192: 1, H0422: 1 and H0506: 1. 4 H6EEU40 757048 14 175-318 AR277: 63,AR283: 52, AR219: 45, AR282: 44, AR104: 43, AR218: 41, AR316: 39, AR089:37, AR313: 37, AR299: 35, AR055: 33, AR240: 33, AR096: 30, AR185: 29,AR300: 28, AR039: 27, AR060: 27, L0741: 8, H0677: 7, L0439: 6, H0052: 5,H0494: 5, L0747: 5, S0007: 4, H0543: 4, H0009: 3, L0771: 3, L0775: 3,H0663: 3, L0665: 3, L0438: 3, H0547: 3, H0521: 3, H0436: 3, L0742: 3,L0748: 3, L0751: 3, S0436: 3, H0556: 2, H0255: 2, S0420: 2, S0358: 2,S0046: 2, L0717: 2, S0222: 2, H0333: 2, H0559: 2, H0318: 2, H0581: 2,H0545: 2, H0620: 2, H0024: 2, H0266: 2, H0617: 2, H0529: 2, L0662: 2,L0653: 2, L0659: 2, L0809: 2, L0664: 2, H0690: 2, H0555: 2, L0743: 2,L0755: 2, L0757: 2, L0759: 2, L0588: 2, H0352: 2, H0624: 1, H0685: 1,H0740: 1, H0295: 1, S0134: 1, H0583: 1, H0656: 1, H0341: 1, S0212: 1,H0484: 1, L3659: 1, S0418: 1, S0356: 1, S0442: 1, S0410: 1, H0729: 1,H0735: 1, H0339: 1, H0619: 1, S0278: 1, H0257: 1, H0069: 1, H0744: 1,H0327: 1, H0023: 1, S0051: 1, T0010: 1, H0031: 1, H0181: 1, H0032: 1,H0169: 1, S0364: 1, H0135: 1, H0163: 1, H0090: 1, H0063: 1, H0087: 1,H0551: 1, H0264: 1, H0488: 1, H0623: 1, H0100: 1, S0438: 1, S0440: 1,L0369: 1, L0770: 1, L0769: 1, L5565: 1, L0761: 1, L0667: 1, L0772: 1,L0641: 1, L0644: 1, L0764: 1, L0773: 1, L0363: 1, L0768: 1, L0794: 1,L0766: 1, L0381: 1, L0803: 1, L0774: 1, L0375: 1, L0806: 1, L0512: 1,L0517: 1, L0666: 1, H0144: 1, H0702: 1, S0148: 1, L0352: 1, H0519: 1,H0593: 1, H0435: 1, H0658: 1, H0539: 1, S0406: 1, H0478: 1, H0631: 1,S0028: 1, S0206: 1, L0744: 1, L0740: 1, L0745: 1, L0749: 1, L0750: 1,L0758: 1, H0445: 1, S0434: 1, L0594: 1, S0194: 1, H0542: 1 and H0423: 1.5 HACAB68 584773 15 135-371 L0748: 4, H0457: 3 and S6022: 1. 6 HACBJ56847112 16 250-327 AR251: 7, AR310: 6, AR265: 6, AR053: 6, AR060: 6,AR182: 6, AR055: 6, AR312: 5, AR309: 5, AR273: 5, AR282: 5, AR061: 5,AR206: 5, AR241: 5, AR194: 5, AR186: 5, AR270: 4, AR213: 4, AR052: 4,AR266: 4, AR218: 4, AR089: 4, AR274: 4, AR253: 4, AR269: 4, AR291: 4,AR248: 4, AR296: 4, AR183: 4, AR240: 4, AR104: 4, AR293: 4, AR205: 4,AR284: 4, AR289: 3, AR313: 3, AR184: 3, AR299: 3, AR247: 3, AR185: 3,AR316: 3, AR231: 3, AR298: 3, AR033: 3, AR243: 3, AR268: 3, AR290: 3,AR283: 3, AR295: 3, AR300: 3, AR246: 3, AR277: 3, AR232: 3, AR175: 3,AR096: 3, AR219: 3, AR177: 3, AR234: 3, AR233: 3, AR275: 3, AR237: 3,AR238: 3, AR285: 3, AR227: 3, AR202: 3, AR263: 3, AR292: 3, AR204: 2,AR286: 2, AR314: 2, AR267: 2, AR280: 2, AR229: 2, AR258: 2, AR039: 2,AR294: 2, AR256: 2, AR259: 2, AR281: 1, AR315: 1, AR26: 1, AR244: 1,AR249: 1, H0661: 1, S0045: 1, H0550: 1, S0280: 1, S0010: 1, H0028: 1,L0764: 1, L0803: 1, L0805: 1, L0665: 1, S0053: 1, H0670: 1, L0748: 1,L0731: 1 and L0581: 1. 7 HADMB15 847116 17 238-300 AR104: 19, AR218: 19,AR219: 16, AR089: 11, AR313: 8, AR055: 8, AR060: 7, AR299: 6, AR282: 5,AR300: 5, AR039: 5, AR240: 5, AR316: 5, AR185: 5, AR277: 4, AR283: 4,AR096: 3, L0595: 2, L0442: 1, L0005: 1, L3653: 1, H0390: 1, H0081: 1,H0024: 1, L0770: 1, L5566: 1, L0651: 1, L0565: 1, L0439: 1, L0747: 1,L0752: 1, H0445: 1, L0592: 1 and L0599: 1. 8 HAGFS57 847120 18 241-405AR055: 7, AR104: 6, AR060: 5, AR277: 4, AR300: 3, AR299: 3, AR096: 3,AR316: 3, AR039: 2, AR185: 2, AR089: 2, AR283: 2, AR218: 2, AR219: 1,AR313: 1, AR240: 1, L0438: 6, L0439: 4, S0360: 3, S0422: 3, H0547: 3,L0747: 3, L0005: 2, S0222: 2, S0002: 2, L0664: 2, L0754: 2, S0434: 2,H0506: 2, H0170: 1, H0171: 1, S0116: 1, S0212: 1, H0580: 1, H0749: 1,H0455: 1, L3655: 1, H0069: 1, H0098: 1, S0010: 1, L0105: 1, H0581: 1,H0263: 1, H0009: 1, L0471: 1, H0099: 1, S0003: 1, H0039: 1, S0036: 1,H0090: 1, H0591: 1, S0426: 1, L0794: 1, L0776: 1, L5622: 1, S0052: 1,H0144: 1, H0682: 1, H0659: 1, H0521: 1, H0555: 1, L0756: 1, H0445: 1 andS0452: 1. 9 HAGHN57 773286 19 900-932 AR313: 12, AR316: 11, AR218: 11,AR185: 11, AR039: 10, AR219: 10, AR299: 10, AR060: 9, AR055: 8, AR277:8, AR282: 8, AR096: 7, AR089: 7, AR300: 7, AR240: 6, AR104: 6, AR283: 4,H0521: 5, L0777: 5, S0376: 4, H0733: 3, H0156: 3, H0519: 3, H0436: 3,L0731: 3, H0656: 2, H0580: 2, H0747: 2, L3816: 2, H0036: 2, L0471: 2,H0090: 2, H0040: 2, H0551: 2, H0494: 2, S0438: 2, S0440: 2, H0529: 2,L0809: 2, H0144: 2, S0374: 2, H0593: 2, H0170: 1, L3643: 1, H0583: 1,H0650: 1, S0418: 1, S0358: 1, S0444: 1, L3645: 1, H0741: 1, H0734: 1,S0045: 1, S0476: 1, H0619: 1, H0586: 1, H0643: 1, H0632: 1, H0486: 1,S0280: 1, H0590: 1, S0010: 1, S0346: 1, H0581: 1, H0231: 1, H0046: 1,H0123: 1, S6028: 1, H0687: 1, S0003: 1, S0214: 1, H0252: 1, H0615: 1,H0212: 1, L0455: 1, S0366: 1, H0163: 1, H0038: 1, H0634: 1, T0067: 1,L0475: 1, H0560: 1, H0561: 1, S0464: 1, H0646: 1, S0426: 1, H0026: 1,L0790: 1, H0520: 1, H0435: 1, S0328: 1, H0539: 1, H0704: 1, S0027: 1,L0439: 1, L0750: 1, L0756: 1, L0757: 1, S0434: 1, L0581: 1, L0595: 1,H0543: 1 and H0423: 1. 10 HAJAA47 534670 20 192-308 H0560: 1, H0561: 1and H0542: 1. 11 HAJAY92 845601 21  12-296 AR060: 184, AR055: 136,AR185: 131, AR299: 118, AR283: 100, AR300: 99, AR277: 94, AR089: 94,AR104: 84, AR282: 79, AR039: 68, AR316: 65, AR240: 60, AR096: 54, AR218:35, AR219: 33, AR313: 33, H0561: 1 and L0758: 1. 12 HAJBV67 866415 22605-1684 AR039: 11, AR219: 10, AR316: 9, AR218: 9, AR089: 9, AR270: 8,AR282: 8, AR283: 8, AR269: 8, AR248: 7, AR299: 7, AR183: 7, AR309: 7,AR277: 7, AR096: 7, AR104: 7, AR313: 7, AR281: 7, AR265: 6, AR249: 6,AR253: 6, AR315: 6, AR300: 6, AR290: 6, AR292: 6, AR202: 6, AR312: 6,AR280: 6, AR175: 6, AR231: 5, AR182: 5, AR185: 5, AR268: 5, AR060: 5,AR294: 5, AR194: 5, AR238: 5, AR247: 4, AR243: 4, AR053: 4, AR267: 4,AR295: 4, AR291: 4, AR055: 4, AR285: 4, AR213: 4, AR052: 4, AR184: 4,AR293: 4, AR296: 3, AR240: 3, AR033: 3, AR310: 3, AR314: 3, AR275: 3,AR246: 3, AR205: 3, AR286: 3, AR271: 3, AR234: 3, AR192: 3, AR298: 3,AR263: 3, AR232: 3, AR256: 3, AR251: 3, AR259: 2, AR284: 2, AR229: 2,AR289: 2, AR226: 2, AR274: 2, AR237: 2, AR258: 2, AR179: 2, AR177: 2,AR233: 2, AR273: 2, AR227: 2, AR204: 2, AR186: 1, AR061: 1, AR241: 1,L0754: 9, S0444: 6, S0442: 5, S0358: 5, H0622: 5, H0624: 4, H0040: 4,L0659: 4, H0144: 4, H0521: 4, H0171: 3, L3499: 3, L2630: 3, H0046: 3,H0658: 3, H0555: 3, H0436: 3, L0758: 3, S0434: 3, H0543: 3, S0418: 2,S0360: 2, S0222: 2, L2499: 2, H0013: 2, H0156: 2, H0575: 2, H0615: 2,H0674: 2, H0616: 2, H0551: 2, H0412: 2, H0623: 2, S0440: 2, H0647: 2,S0422: 2, H0529: 2, L0666: 2, L2263: 2, S0374: 2, S0380: 2, S0146: 2,L0740: 2, L0731: 2, L0759: 2, S0436: 2, L0362: 2, H0556: 1, L3644: 1,S0114: 1, T0049: 1, L0002: 1, L2910: 1, S0282: 1, L2300: 1, S0356: 1,S0354: 1, S0408: 1, S0410: 1, L3709: 1, H0637: 1, H0742: 1, H0722: 1,S0046: 1, S0132: 1, S0300: 1, L2744: 1, L0717: 1, H0411: 1, H0431: 1,H0586: 1, H0587: 1, L2491: 1, L2647: 1, H0036: 1, H0004: 1, S0010: 1,H0318: 1, H0581: 1, H0251: 1, H0596: 1, L0471: 1, H0024: 1, H0014: 1,H0375: 1, H0266: 1, S0003: 1, S0214: 1, H0688: 1, T0023: 1, H0553: 1,L0055: 1, H0032: 1, S0036: 1, H0090: 1, H0591: 1, H0038: 1, T0067: 1,H0477: 1, H0488: 1, H0059: 1, H0561: 1, L0369: 1, L3905: 1, L0662: 1,L0766: 1, L0388: 1, L0774: 1, L0775: 1, L0606: 1, L0661: 1, L0526: 1,L0809: 1, L0665: 1, L2653: 1, L3665: 1, L3811: 1, H0519: 1, S0126: 1,H0683: 1, H0684: 1, H0659: 1, H0672: 1, H0710: 1, H0522: 1, S3014: 1,S0028: 1, L0752: 1, H0595: 1, S0394: 1, L0596: 1, L0589: 1, L0485: 1,L0595: 1, H0667: 1, S0242: 1, S0194: 1, H0423: 1, H0422: 1, S0384: 1,H0506: 1 and H0352: 1. 13 HATCD80 826098 23 296-409 AR316: 50, AR055: 4,AR277: 3, AR060: 3, AR300: 3, AR282: 3, AR283: 2, AR218: 2, AR039: 1,AR104: 1, AR089: 1, AR240: 1, AR299: 1, AR185: 1, H0156: 1 and H0038: 1.14 HATEH20 836056 24  93-221 AR055: 7, AR060: 6, AR218: 6, AR185: 5,AR089: 5, AR299: 4, AR313: 4, AR240: 4, AR316: 4, AR300: 4, AR283: 4,AR096: 3, AR039: 3, AR282: 3, AR104: 3, AR277: 2, AR219: 1, L0439: 14,L0740: 13, H0046: 10, H0556: 9, L0752: 9, H0052: 7, H0617: 7, L0748: 7,L0747: 7, L0758: 7, S0222: 6, L0809: 6, L0754: 6, S0049: 5, H0620: 5,L0769: 5, L0766: 5, L0663: 5, H0144: 5, L0438: 5, L0741: 5, L0731: 5,S0436: 5, H0657: 4, S0278: 4, H0599: 4, L0163: 4, H0266: 4, S0002: 4,L0771: 4, L0804: 4, L0659: 4, H0521: 4, L0742: 4, L0743: 4, L0751: 4,L0753: 4, L0759: 4, S0444: 3, H0728: 3, H0618: 3, S0010: 3, H0050: 3,L0471: 3, S0051: 3, T0010: 3, S6028: 3, H0551: 3, H0494: 3, S0144: 3,H0529: 3, L0763: 3, L0770: 3, L0637: 3, L0775: 3, L0655: 3, L0666: 3,S0330: 3, H0696: 3, L0757: 3, H0265: 2, H0716: 2, H0656: 2, S0418: 2,S0442: 2, H0733: 2, L0149: 2, H0333: 2, H0486: 2, H0427: 2, H0042: 2,H0457: 2, H0041: 2, S0003: 2, T0006: 2, S0364: 2, H0124: 2, S0366: 2,H0135: 2, S0038: 2, S0422: 2, L0638: 2, L5575: 2, L5566: 2, L0372: 2,L0662: 2, L0794: 2, L0776: 2, L0789: 2, S0374: 2, H0519: 2, H0658: 2,H0660: 2, S0152: 2, S0406: 2, H0727: 2, L0485: 2, L0599: 2, L0601: 2,H0506: 2, S0040: 1, H0713: 1, H0740: 1, H0650: 1, H0341: 1, S0212: 1,S0282: 1, H0663: 1, H0459: 1, H0638: 1, S0420: 1, L0617: 1, S0360: 1,S0408: 1, H0741: 1, H0735: 1, H0734: 1, H0208: 1, S0132: 1, H0645: 1,H0370: 1, L0622: 1, L0623: 1, H0013: 1, S0280: 1, H0156: 1, L0021: 1,H0097: 1, H0575: 1, H0036: 1, H0590: 1, S0346: 1, H0318: 1, H0230: 1,H0596: 1, H0597: 1, H0231: 1, H0150: 1, H0009: 1, N0006: 1, H0565: 1,H0569: 1, H0242: 1, H0012: 1, H0024: 1, H0373: 1, H0051: 1, H0083: 1,H0267: 1, H0292: 1, H0428: 1, H0604: 1, H0553: 1, H0181: 1, H0168: 1,H0169: 1, H0708: 1, H0163: 1, H0090: 1, T0067: 1, H0264: 1, S0386: 1,S0112: 1, L0351: 1, L0564: 1, T0042: 1, H0561: 1, S0370: 1, S0142: 1,S0344: 1, L0640: 1, L0761: 1, L0667: 1, L0373: 1, L0646: 1, L0641: 1,L0374: 1, L0764: 1, L0773: 1, L0521: 1, L0626: 1, L0533: 1, L0803: 1,L0651: 1, L0805: 1, L0661: 1, L0657: 1, L0634: 1, L0542: 1, L0783: 1,L0529: 1, L0543: 1, L5623: 1, L0787: 1, L0665: 1, L3811: 1, L3825: 1,H0520: 1, H0547: 1, S0380: 1, H0522: 1, H0436: 1, H0576: 1, L0609: 1,L0744: 1, L0745: 1, L0749: 1, L0786: 1, L0777: 1, L0755: 1, H0444: 1,S0434: 1, L0480: 1, L0584: 1, L0595: 1, S0011: 1, H0422: 1 and H0008: 1.15 HBAGD86 838799 25 521-580 AR219: 7, AR218: 4, AR313: 4, AR104: 4,AR039: 3, AR299: 3, AR282: 2, AR300: 2, AR096: 2, AR316: 2, AR277: 1,AR240: 1, AR089: 1, L0809: 4, L0766: 3, L0439: 3, H0624: 2, H0411: 2,L0794: 2, L0749: 2, L0756: 2, L0005: 1, L3649: 1, S0476: 1, H0599: 1,L0471: 1, S0051: 1, T0010: 1, H0266: 1, S0150: 1, S0422: 1, L0637: 1,L0765: 1, L0803: 1, L0783: 1, L5622: 1, H0144: 1, H0672: 1, S0392: 1,L0748: 1, L0754: 1, L0779: 1, L0777: 1, L0731: 1 and L0759: 1. 16HBGBC29 691473 26 1016-1024 AR299: 5, AR218: 5, AR313: 4, AR300: 4,AR055: 4, AR060: 4, AR277: 3, AR316: 3, AR089: 3, AR185: 3, AR096: 3,AR039: 3, AR219: 3, AR104: 3, AR240: 3, AR282: 2, AR283: 2, L0731: 20,L0747: 7, L0794: 6, L0764: 4, L0803: 4, L0759: 4, L0662: 3, L0774: 3,L0749: 3, L0756: 3, S0436: 3, S0360: 2, H0156: 2, H0046: 2, H0181: 2,L0766: 2, L0659: 2, L0809: 2, L0438: 2, S0126: 2, H0658: 2, L0439: 2,L0754: 2, L0777: 2, L0755: 2, L0757: 2, L0604: 2, S0242: 2, S0442: 1,S0376: 1, S0408: 1, L0717: 1, H0270: 1, H0263: 1, H0597: 1, H0123: 1,H0617: 1, H0551: 1, S0440: 1, H0647: 1, L0770: 1, L0769: 1, L0638: 1,L0775: 1, L0651: 1, L0527: 1, L0526: 1, L0789: 1, L0666: 1, L0665: 1,H0547: 1, H0435: 1, H0648: 1, S0330: 1, S0406: 1, H0627: 1, L0750: 1,L0780: 1, L0752: 1, L0758: 1, L0366: 1 and H0293: 1. 17 HBGNC72 89213127 550-780 AR096: 11, AR240: 11, AR316: 9, AR218: 9, AR089: 8, AR282: 8,AR219: 8, AR055: 7, AR060: 7, AR299: 6, AR104: 6, AR039: 6, AR185: 6,AR313: 6, AR283: 6, AR300: 5, AR277: 5, H0617: 5, H0547: 3, L0751: 3,L0779: 3, H0618: 2, H0052: 2, H0135: 2, H0100: 2, L0637: 2, L0764: 2,H0520: 2, H0593: 2, H0543: 2, H0265: 1, H0556: 1, H0585: 1, H0255: 1,H0664: 1, S0420: 1, S0442: 1, H0637: 1, H0733: 1, S0045: 1, H0614: 1,H0485: 1, H0486: 1, H0374: 1, S0049: 1, H0086: 1, H0674: 1, L0770: 1,L0769: 1, L3905: 1, L0662: 1, L0794: 1, L0766: 1, L0803: 1, L0805: 1,L0653: 1, L0654: 1, L0636: 1, L0783: 1, L5622: 1, L5623: 1, L0787: 1,L0663: 1, H0519: 1, H0521: 1, H0555: 1, H0436: 1, S0028: 1, L0741: 1,L0758: 1, S0276: 1 and H0352: 1. 18 HBHAA05 603174 28 110-286 AR313: 74,AR039: 45, AR299: 34, AR089: 33, AR185: 31, AR277: 29, AR096: 26, AR300:26, AR240: 22, AR316: 20, AR218: 17, AR060: 15, AR219: 14, AR104: 14,AR282: 11, AR055: 9, AR283: 6, S0029: 1 19 HBHAA81 846465 29  28-639AR289: 34, AR291: 33, AR283: 32, AR055: 32, AR294: 26, AR266: 26, AR286:26, AR256: 23, AR285: 21, AR293: 19, AR259: 17, AR295: 16, AR292: 15,AR298: 14, AR258: 14, AR296: 12, AR284: 11, AR104: 10, AR033: 9, AR186:9, AR202: 7, AR206: 7, AR246: 7, AR204: 7, AR241: 6, AR194: 5, AR198: 4,AR244: 4, AR251: 4, AR060: 4, AR061: 4, AR282: 4, AR052: 4, AR053: 4,AR205: 4, AR309: 4, AR316: 3, AR182: 3, AR312: 3, AR192: 3, AR273: 3,AR229: 3, AR183: 3, AR310: 3, AR271: 3, AR213: 3, AR248: 3, AR270: 3,AR277: 2, AR185: 2, AR275: 2, AR299: 2, AR269: 2, AR300: 2, AR247: 2,AR267: 2, AR175: 2, AR089: 2, AR313: 2, AR265: 2, AR268: 2, AR237: 2,AR096: 1, AR232: 1, AR039: 1, AR240: 1, AR179: 1, AR231: 1, AR234: 1,H0599: 8, S0366: 7, L0485: 6, H0733: 5, H0734: 5, L0769: 5, H0735: 4,H0729: 3, H0728: 3, H0619: 2, H0706: 2, L0661: 2, L0756: 2, L0759: 2,S0282: 1, S0029: 1, S0222: 1, L0622: 1, H0122: 1, S0010: 1, H0196: 1,H0012: 1, H0200: 1, H0373: 1, S6028: 1, S0364: 1, S0036: 1, S0294: 1,L0770: 1, L0638: 1, L5565: 1, L0657: 1, L0809: 1, L0789: 1, L0791: 1,L0438: 1, L0439: 1, L0750: 1, L0777: 1, S0260: 1, L0604: 1 and S0460: 1.20 HBIAC29 831751 30 1036-1125 AR089: 25, AR218: 17, AR104: 14, AR219:13, AR313: 12, AR316: 11, AR060: 11, AR096: 10, AR055: 10, AR299: 9,AR185: 9, AR039: 9, AR240: 8, AR282: 8, AR300: 8, AR283: 6, AR277: 5,L0105: 11, L0745: 5, L0770: 4, L0794: 4, L0777: 4, S0003: 3, L0766: 3,L0806: 3, L0809: 3, L0740: 3, L0751: 3, L0749: 3, S0376: 2, S0360: 2,L0598: 2, L0776: 2, L0666: 2, L0663: 2, S0126: 2, H0659: 2, H0658: 2,S0406: 2, H0436: 2, S3014: 2, L0754: 2, L0756: 2, L0604: 2, H0624: 1,H0265: 1, S0116: 1, H0669: 1, H0331: 1, L0586: 1, S0049: 1, H0597: 1,L0471: 1, H0024: 1, S0214: 1, H0169: 1, L0455: 1, H0135: 1, S0422: 1,L0451: 1, L0772: 1, L0764: 1, L0765: 1, L0773: 1, L0387: 1, L0804: 1,L0805: 1, L0657: 1, L0659: 1, L0526: 1, L0783: 1, L0529: 1, L0787: 1,L0788: 1, L0664: 1, L0665: 1, L0748: 1, L0779: 1, L0731: 1, L0599: 1,H0543: 1 and H0423: 1. 21 HBJAB02 837309 31  84-188 AR282: 3, AR277: 1,AR039: 1, AR316: 1, S0434: 5, L0794: 3, H0255: 2, H0318: 2, H0251: 2,L0764: 2, L0628: 2, L0809: 2, L0665: 2, H0658: 2, S0406: 2, L0361: 2,H0265: 1, H0685: 1, H0657: 1, H0483: 1, S0420: 1, S0442: 1, S0358: 1,H0729: 1, H0734: 1, S0132: 1, S0222: 1, T0082: 1, H0150: 1, H0083: 1,S0214: 1, H0252: 1, H0628: 1, T0041: 1, S0344: 1, H0529: 1, L0520: 1,L0535: 1, L0662: 1, L0387: 1, L0375: 1, L0518: 1, L0666: 1, L0663: 1,H0726: 1, H0519: 1, H0670: 1, H0660: 1, L0602: 1, L0747: 1, L0777: 1,L0601: 1, S0276: 1, H0423: 1 and H0422: 1. 22 HBJAC40 841235 32 329-370AR104: 23, AR060: 6, AR055: 6, AR283: 5, AR185: 5, AR282: 4, AR313: 4,AR299: 4, AR316: 4, AR277: 3, AR096: 3, AR240: 3, AR219: 2, AR089: 2,AR300: 2, AR039: 2, AR218: 2, L0439: 18, H0052: 12, L0741: 8, L0438: 6,S0051: 5, H0556: 4, L0769: 4, L0774: 4, S0474: 3, H0622: 3, S0036: 3,L3905: 3, H0261: 2, H0318: 2, H0194: 2, L0471: 2, H0538: 2, L0749: 2,L0757: 2, L0758: 2, S0436: 2, L0593: 2, H0624: 1, H0265: 1, S0342: 1,H0717: 1, H0650: 1, H0657: 1, S0212: 1, S0282: 1, H0730: 1, S0045: 1,S0476: 1, H0619: 1, S0222: 1, H0455: 1, H0559: 1, H0075: 1, H0253: 1,H0251: 1, H0544: 1, L0158: 1, H0012: 1, S0050: 1, L0163: 1, H0083: 1,H0594: 1, H0615: 1, T0006: 1, H0708: 1, H0087: 1, H0056: 1, S0038: 1,H0494: 1, S0450: 1, S0144: 1, L0770: 1, L4747: 1, L0639: 1, L0761: 1,L0775: 1, L0805: 1, L0635: 1, L5622: 1, L0788: 1, S0428: 1, S0044: 1,L0612: 1, L0742: 1, L0748: 1, L0779: 1, L0777: 1, S0011: 1 and H0136: 1.23 HBJCR46 815649 33  589-2787 L0794: 11, L0803: 10, L0779: 10, H0038:9, L0777: 9, L0758: 9, S0358: 6, L0809: 5, S0408: 4, H0616: 4, L0748: 4,L0439: 4, L0591: 4, S0282: 3, L0789: 3, L0666: 3, L0438: 3, L0756: 3,H0036: 2, H0196: 2, H0046: 2, H0154: 2, L0163: 2, H0213: 2, S0036: 2,L0804: 2, L0774: 2, L0655: 2, L0656: 2, S0374: 2, S0126: 2, S0328: 2,S0152: 2, H0521: 2, S0406: 2, L0731: 2, L0588: 2, L0485: 2, S0026: 2,H0543: 2, H0170: 1, H0171: 1, H0713: 1, S6024: 1, H0650: 1, H0656: 1,S0116: 1, H0341: 1, H0638: 1, S0442: 1, S0354: 1, S0360: 1, H0580: 1,S0045: 1, H0619: 1, H0437: 1, S0222: 1, H0333: 1, H0574: 1, H0486: 1,H0575: 1, H0590: 1, H0618: 1, H0253: 1, H0318: 1, H0581: 1, H0230: 1,H0597: 1, H0544: 1, H0178: 1, H0123: 1, H0050: 1, S0050: 1, H0014: 1,S6028: 1, H0266: 1, S0003: 1, H0033: 1, H0032: 1, H0673: 1, H0598: 1,H0163: 1, H0040: 1, H0551: 1, H0623: 1, H0100: 1, T0041: 1, H0561: 1,S0438: 1, H0641: 1, S0344: 1, S0002: 1, S0426: 1, L0769: 1, L0800: 1,L0641: 1, L0766: 1, L0775: 1, L0375: 1, L0653: 1, L0634: 1, L0659: 1,L0783: 1, L0787: 1, L0663: 1, L0664: 1, L0665: 1, H0725: 1, H0670: 1,H0522: 1, H0436: 1, H0540: 1, S0027: 1, L0740: 1, L0751: 1, L0747: 1,L0749: 1, L0786: 1, L0780: 1, L0752: 1, L0757: 1, L0608: 1, L0604: 1,S0192: 1 and S0276: 1. 24 HBJDW56 520401 34 121-147 AR055: 8, AR060: 7,AR282: 6, AR104: 5, AR313: 5, AR185: 5, AR300: 4, AR089: 4, AR299: 4,AR240: 4, AR039: 4, AR219: 4, AR316: 3, AR096: 3, AR283: 3, AR218: 3,AR277: 2, H0318: 1 25 HBJEL16 847030 35 115-225 H0046: 2, H0009: 2,H0090: 2, H0494: 2, L0438: 2, H0547: 2, H0521: 2, L0439: 2, L0777: 2,H0543: 2, H0556: 1, S0342: 1, S0045: 1, H0619: 1, H0632: 1, H0013: 1,H0156: 1, L0021: 1, H0575: 1, H0318: 1, S0003: 1, L0483: 1, H0628: 1,H0623: 1, H0561: 1, L0761: 1, L0803: 1, L0804: 1, L0659: 1, L0382: 1,H0144: 1, H0539: 1, S0152: 1, H0478: 1, H0631: 1, L0741: 1, L0740: 1 andL0591: 1. 26 HBJKD16 853358 36  78-173 AR172: 63, AR171: 62, AR215: 61,AR274: 50, AR216: 48, AR213: 43, AR214: 41, AR272: 41, AR169: 41, AR224:37, AR225: 37, AR217: 37, AR254: 36, AR205: 36, AR170: 35, AR243: 35,AR168: 35, AR247: 34, AR245: 32, AR312: 32, AR221: 32, AR212: 31, AR161:29, AR222: 28, AR162: 28, AR311: 27, AR308: 27, AR163: 26, AR275: 26,AR165: 25, AR164: 24, AR313: 23, AR053: 23, AR166: 23, AR223: 21, AR039:20, AR089: 20, AR309: 19, AR096: 19, AR242: 18, AR253: 18, AR240: 17,AR289: 16, AR266: 16, AR283: 16, AR263: 16, AR193: 16, AR316: 16, AR264:16, AR204: 16, AR250: 15, AR282: 15, AR201: 15, AR277: 15, AR207: 14,AR291: 14, AR246: 14, AR200: 13, AR198: 13, AR271: 12, AR299: 12, AR300:12, AR195: 12, AR185: 12, AR104: 12, AR290: 11, AR192: 11, AR173: 11,AR255: 11, AR257: 11, AR060: 11, AR197: 11, AR252: 10, AR180: 10, AR297:10, AR179: 10, AR210: 10, AR061: 10, AR181: 9, AR296: 9, AR199: 9,AR270: 9, AR269: 9, AR178: 9, AR183: 9, AR268: 8, AR055: 8, AR177: 8,AR262: 8, AR236: 8, AR288: 8, AR211: 8, AR188: 7, AR267: 7, AR293: 7,AR219: 7, AR285: 7, AR256: 7, AR294: 7, AR174: 7, AR176: 7, AR189: 7,AR033: 7, AR261: 7, AR218: 7, AR287: 6, AR175: 6, AR196: 6, AR231: 6,AR203: 6, AR286: 5, AR235: 5, AR190: 5, AR230: 5, AR234: 5, AR191: 5,AR182: 5, AR260: 5, AR258: 4, AR295: 4, AR237: 4, AR233: 4, AR229: 4,AR238: 4, AR239: 3, AR226: 3, AR232: 2, AR227: 2, AR228: 2, L0766: 9,L0439: 9, L0747: 6, L2528: 5, L0777: 5, H0673: 4, L0438: 4, L0758: 4,L0362: 4, S0116: 3, L0748: 3, L0752: 3, H0445: 3, H0156: 2, T0010: 2,H0615: 2, H0038: 2, H0616: 2, H0264: 2, H0646: 2, L0761: 2, L0776: 2,L0750: 2, L0779: 2, S0436: 2, L0593: 2, S0242: 2, H0222: 1, H0740: 1,H0657: 1, H0661: 1, H0663: 1, L2293: 1, H0589: 1, S0444: 1, H0340: 1,L3646: 1, H0580: 1, H0749: 1, H0393: 1, H0549: 1, S0222: 1, H0574: 1,H0486: 1, H0013: 1, H0069: 1, L0021: 1, S0010: 1, H0318: 1, S0474: 1,H0046: 1, L0471: 1, H0090: 1, L0638: 1, L0646: 1, L0764: 1, L0521: 1,L0364: 1, L0774: 1, L0659: 1, L0543: 1, L5622: 1, L0792: 1, L0666: 1,L0664: 1, L0665: 1, S0428: 1, L2657: 1, L2652: 1, L3663: 1, L2262: 1,H0435: 1, L3832: 1, L0741: 1, L0749: 1, S0434: 1, L0588: 1, H0422: 1,L0698: 1 and L2359: 1. 27 HBMBM96 561935 37 170-184 AR313: 45, AR039:38, AR277: 36, AR299: 25, AR096: 23, AR185: 22, AR089: 21, AR219: 19,AR300: 18, AR218: 18, AR104: 17, AR316: 16, AR060: 13, AR240: 12, AR282:11, AR055: 9, AR283: 4, L0747: 2, H0392: 1, H0574: 1, H0421: 1, L0662:1, L0666: 1, S0404: 1, L0744: 1 and H0543: 1. 28 HBMTM11 589515 38125-220 AR039: 17, AR313: 13, AR219: 11, AR055: 9, AR218: 9, AR104: 8,AR096: 8, AR089: 8, AR316: 8, AR299: 7, AR300: 7, AR277: 7, AR060: 7,AR282: 6, AR185: 6, AR240: 6, AR283: 2, S0422: 14, L0754: 14, L0766: 13,L0740: 7, L0779: 6, L0755: 5, H0591: 4, L0756: 4, S0354: 3, L0663: 3,L0438: 3, L0777: 3, L0752: 3, L0362: 3, H0423: 3, H0624: 2, S0218: 2,S0212: 2, H0638: 2, S0360: 2, S0222: 2, H0562: 2, H0014: 2, H0615: 2,H0412: 2, S0002: 2, L0638: 2, L0764: 2, S0406: 2, H0555: 2, L0439: 2,L0745: 2, L0753: 2, H0543: 2, H0170: 1, L3643: 1, S0040: 1, H0713: 1,H0740: 1, S0134: 1, S0116: 1, H0669: 1, S0442: 1, S0444: 1, H0637: 1,H0729: 1, H0734: 1, S0046: 1, H0747: 1, H0749: 1, L0717: 1, S6016: 1,H0497: 1, H0333: 1, L3816: 1, H0632: 1, H0485: 1, H0486: 1, H0013: 1,H0427: 1, H0156: 1, L0021: 1, H0122: 1, H0318: 1, H0596: 1, H0546: 1,H0046: 1, H0457: 1, H0123: 1, H0375: 1, S6028: 1, S0250: 1, H0428: 1,H0553: 1, H0644: 1, H0674: 1, H0634: 1, H0063: 1, H0264: 1, H0623: 1,H0561: 1, H0646: 1, H0529: 1, L0761: 1, L0662: 1, L0767: 1, L0649: 1,L0774: 1, L0775: 1, L0375: 1, L0805: 1, L0776: 1, L0658: 1, L0518: 1,L0783: 1, L0809: 1, L0647: 1, L0367: 1, L0789: 1, L0792: 1, L0666: 1,L0664: 1, H0519: 1, H0690: 1, H0670: 1, H0648: 1, S0330: 1, S0378: 1,H0709: 1, H0436: 1, S0390: 1, S0028: 1, L0758: 1, L0759: 1, S0434: 1,S0436: 1, H0668: 1, S0412: 1 and S0424: 1. 29 HBMUH74 866160 39 344-430AR218: 12, AR055: 8, AR060: 7, AR104: 7, AR219: 5, AR240: 5, AR299: 5,AR096: 4, AR316: 4, AR300: 4, AR039: 4, AR089: 3, AR283: 3, AR185: 3,AR313: 3, AR282: 2, AR277: 2, L0754: 3, L0777: 3, L0439: 2, S0116: 1,H0341: 1, H0661: 1, H0038: 1, H0412: 1, L0761: 1, L0667: 1, L0764: 1,L0788: 1, H0435: 1, L0749: 1, L0779: 1 and L0758: 1. 30 HBQAB79 81054240 190-225 AR055: 7, AR218: 7, AR060: 6, AR039: 6, AR300: 5, AR185: 5,AR313: 5, AR240: 4, AR299: 4, AR089: 4, AR096: 3, AR316: 3, AR283: 3,AR104: 2, AR219: 2, AR277: 2, AR282: 1, H0229: 1 31 HBSAK32 856387 41447-590 AR277: 18, AR104: 14, AR218: 14, AR219: 13, AR299: 13, AR313:12, AR316: 12, AR089: 12, AR185: 12, AR283: 11, AR060: 11, AR039: 11,AR096: 11, AR240: 10, AR055: 10, AR282: 10, AR300: 7, L0790: 2, H0170:1, H0381: 1, S0001: 1, S0282: 1, L0021: 1, S0112: 1, L0640: 1, L0766: 1,L0774: 1, L0651: 1, L0517: 1, L0783: 1, L0809: 1, L0519: 1, L0743: 1,L0751: 1, L0747: 1, L0749: 1, L0750: 1, L0777: 1, L0755: 1, L0758: 1 andL0759: 1. 32 HBXCX15 637542 42 72-77 S0038: 3, H0438: 1, L0363: 1 andS0053: 1. 33 HCDCY76 837972 43 860-967 AR219: 7, AR218: 6, AR055: 2,AR282: 2, AR060: 2, AR299: 1, AR104: 1, AR185: 1, AR240: 1, AR277: 1,L1430: 5, L0770: 2, L0754: 2, L0747: 2, L0777: 2, S0360: 1, S0045: 1,H0486: 1, H0616: 1, L0803: 1, L0775: 1, L0783: 1, L0787: 1, L0789: 1,L0750: 1, S0194: 1 and S0276: 1. 34 HCDDL48 839743 44 333-455 AR282: 5,AR055: 5, AR060: 4, AR240: 3, AR283: 3, AR300: 2, AR316: 2, AR104: 2,AR039: 2, AR313: 2, AR185: 1, AR218: 1, AR089: 1, AR299: 1, AR219: 1,AR096: 1, H0251: 1 35 HCE1G78 761204 45  77-841 AR277: 13, AR060: 9,AR104: 9, AR218: 8, AR055: 8, AR282: 8, AR299: 8, AR283: 7, AR039: 7,AR185: 6, AR089: 6, AR219: 6, AR316: 5, AR300: 5, AR096: 5, AR313: 5,AR240: 5, L0439: 8, S0356: 2, L0803: 2, L0809: 2, L0666: 2, L0752: 2,S0442: 1, H0052: 1, H0194: 1, H0617: 1, H0040: 1, H0100: 1, L5565: 1,L0774: 1, L0787: 1 and L0593: 1. 36 HCE5F78 838101 46 566-664 H0052: 2and H0445: 2. 37 HCEDR26 771144 47 177-344 AR313: 59, AR039: 47, AR277:33, AR299: 28, AR185: 25, AR096: 23, AR089: 23, AR300: 20, AR219: 19,AR240: 17, AR316: 16, AR104: 15, AR282: 13, AR218: 13, AR060: 13, AR283:10, AR055: 10, H0052: 2, H0018: 1, H0264: 1 and L0700: 1. 38 HCEEQ25531784 48 111-182 AR039: 8, AR313: 7, AR185: 7, AR055: 7, AR300: 6,AR060: 6, AR240: 6, AR218: 6, AR089: 5, AR299: 5, AR104: 5, AR096: 4,AR316: 4, AR277: 3, AR282: 3, AR283: 3, AR219: 3, H0052: 1 and H0144: 1.39 HCEEU18 688041 49 209-340 AR313: 46, AR039: 35, AR299: 24, AR219: 21,AR277: 21, AR089: 20, AR096: 19, AR185: 19, AR218: 16, AR316: 14, AR300:13, AR104: 13, AR240: 12, AR060: 11, AR282: 10, AR055: 9, AR283: 5,H0052: 1 40 HCEGG08 844506 50 1114-1197 AR240: 6, AR282: 6, AR104: 5,AR060: 5, AR055: 4, AR089: 4, AR277: 4, AR096: 4, AR283: 3, AR039: 3,AR300: 3, AR299: 3, AR313: 3, AR185: 2, AR219: 2, AR316: 2, AR218: 2,L0439: 15, H0052: 11, S0007: 9, L0438: 6, L0731: 6, L0779: 5, L0754: 4,H0550: 3, L0769: 3, S0126: 3, L0743: 3, H0194: 2, H0687: 2, H0623: 2,L0768: 2, L0776: 2, L0659: 2, L0666: 2, L0663: 2, H0689: 2, S0330: 2,L0748: 2, L0786: 2, L0777: 2, L0752: 2, L0758: 2, L0608: 2, H0352: 2,H0662: 1, S0356: 1, S0354: 1, S0444: 1, S0045: 1, S0476: 1, H0441: 1,H0431: 1, H0333: 1, H0642: 1, H0575: 1, H0590: 1, T0048: 1, H0150: 1,H0024: 1, S0050: 1, S0388: 1, H0252: 1, H0039: 1, H0135: 1, H0038: 1,H0264: 1, H0494: 1, L0770: 1, L4747: 1, L0372: 1, L0646: 1, L0521: 1,L0794: 1, L0803: 1, L0775: 1, L0653: 1, L0661: 1, L0807: 1, L0657: 1,L0809: 1, L0792: 1, L0664: 1, L2258: 1, H0144: 1, L0352: 1, H0519: 1,H0593: 1, H0658: 1, H0672: 1, H0539: 1, S0406: 1, L0751: 1, L0749: 1,L0756: 1, L0753: 1, H0506: 1 and L2357: 1. 41 HCFLN88 610000 51 101-178S0410: 22, L0770: 9, L0748: 9, L0769: 7, L0776: 6, L0659: 6, H0424: 5,L0761: 5, L0731: 5, H0486: 4, L0803: 4, L0809: 4, L0666: 4, H0696: 4,L0754: 4, L0779: 4, L0758: 4, H0729: 3, H0618: 3, H0135: 3, L0637: 3,L0771: 3, L0766: 3, L0805: 3, L0665: 3, L0751: 3, H0542: 3, H0341: 2,H0402: 2, S0358: 2, S0376: 2, S0360: 2, H0747: 2, S0132: 2, L3109: 2,L0717: 2, H0592: 2, H0253: 2, S0010: 2, H0052: 2, H0545: 2, H0050: 2,H0617: 2, H0087: 2, H0551: 2, H0100: 2, H0560: 2, L0763: 2, L5565: 2,L0646: 2, L0764: 2, L0655: 2, L0663: 2, L2260: 2, S0374: 2, H0414: 2,S0406: 2, H0436: 2, L0743: 2, L0740: 2, L0749: 2, L0755: 2, L0757: 2,L0759: 2, H0445: 2, H0136: 2, H0543: 2, H0423: 2, H0352: 2, H0170: 1,H0171: 1, H0225: 1, H0713: 1, S0218: 1, L0785: 1, H0692: 1, S0212: 1,H0483: 1, H0254: 1, H0305: 1, S0356: 1, S0442: 1, S0444: 1, S0408: 1,H0619: 1, H0393: 1, H0406: 1, H0370: 1, H0249: 1, H0101: 1, H0250: 1,S0280: 1, H0599: 1, H0575: 1, H0706: 1, T0048: 1, H0318: 1, S0474: 1,H0581: 1, T0115: 1, H0009: 1, H0572: 1, H0024: 1, S0051: 1, H0271: 1,H0288: 1, T0006: 1, H0213: 1, H0553: 1, H0644: 1, S0364: 1, H0163: 1,H0090: 1, H0264: 1, H0488: 1, S0112: 1, H0494: 1, H0652: 1, S0344: 1,S0002: 1, S0426: 1, L4497: 1, L5575: 1, L3905: 1, L5566: 1, L0772: 1,L0641: 1, L0645: 1, L0773: 1, L0650: 1, L0774: 1, L0775: 1, L0378: 1,L0806: 1, L0783: 1, L5622: 1, L0790: 1, L0664: 1, L3827: 1, H0547: 1,H0519: 1, S0126: 1, H0711: 1, H0672: 1, S0330: 1, H0521: 1, S0392: 1,S0037: 1, L0742: 1, L0439: 1, L0745: 1, L0747: 1, L0750: 1, L0777: 1,S0436: 1, L0485: 1, L0608: 1, S0011: 1, H0653: 1 and H0422: 1. 42HCHAB84 834326 52 304-747 AR313: 37, AR039: 34, AR104: 24, AR300: 24,AR277: 23, AR096: 23, AR185: 20, AR089: 20, AR299: 19, AR219: 18, AR218:17, AR316: 16, AR240: 16, AR282: 13, AR283: 9, AR060: 8, AR055: 7,S0354: 9, S0358: 3, H0494: 3, S0476: 2, S0474: 2, S0438: 2, H0519: 2,H0521: 2, L0754: 2, H0170: 1, S0040: 1, S0114: 1, H0484: 1, H0483: 1,H0255: 1, S0376: 1, S0444: 1, S0408: 1, S0046: 1, H0619: 1, H0549: 1,H0042: 1, H0581: 1, H0052: 1, H0083: 1, S0440: 1, L0773: 1, L0517: 1,L0383: 1, S0374: 1, S0152: 1, S3014: 1, L0751: 1, L0759: 1, S0434: 1,S0436: 1, H0543: 1 and H0422: 1. 43 HCMSX51 788643 53 539-781 L0740: 16,L0745: 7, L0439: 6, L0438: 4, H0547: 4, L0750: 4, L0759: 4, H0619: 3,H0618: 3, L0770: 3, L3828: 3, L0749: 3, L0758: 3, H0393: 2, H0599: 2,H0083: 2, H0124: 2, H0623: 2, H0100: 2, L3905: 2, L0794: 2, L0809: 2,L3825: 2, L3829: 2, S0406: 2, S0027: 2, L0743: 2, L0746: 2, L0777: 2,L0603: 2, S0040: 1, L2879: 1, L2906: 1, S0420: 1, S0442: 1, S0358: 1,L3311: 1, L3485: 1, H0261: 1, H0392: 1, H0013: 1, H0250: 1, H0590: 1,H0196: 1, H0545: 1, H0046: 1, H0123: 1, H0620: 1, S0051: 1, S0250: 1,H0617: 1, S0036: 1, H0135: 1, H0634: 1, H0087: 1, H0269: 1, H0561: 1,H0509: 1, H0646: 1, S0426: 1, L0763: 1, L0769: 1, L3904: 1, L0662: 1,L0363: 1, L0767: 1, L0768: 1, L0650: 1, L0375: 1, L0806: 1, L0776: 1,L0657: 1, L0787: 1, L4559: 1, L0664: 1, L2260: 1, H0520: 1, L3831: 1,H0670: 1, H0518: 1, L3834: 1, H0704: 1, H0436: 1, L0747: 1, L0780: 1,L0608: 1, L0595: 1 and H0423: 1. 44 HCNCO11 775086 54 101-145 AR055: 2,AR060: 2, AR277: 1, AR282: 1, H0597: 1 45 HCNSD29 862314 55 1145-1240AR252: 128, AR253: 67, AR245: 63, AR272: 55, AR308: 49, AR246: 47,AR263: 46, AR212: 40, AR053: 37, AR243: 35, AR312: 34, AR254: 33, AR275:33, AR205: 33, AR309: 32, AR264: 31, AR250: 31, AR197: 31, AR271: 29,AR224: 26, AR195: 26, AR311: 26, AR200: 26, AR223: 26, AR201: 25, AR198:25, AR219: 23, AR274: 22, AR210: 22, AR172: 21, AR218: 21, AR222: 21,AR225: 20, AR221: 20, AR268: 19, AR104: 19, AR096: 18, AR240: 17, AR188:17, AR313: 17, AR199: 17, AR213: 17, AR203: 16, AR242: 16, AR039: 15,AR316: 15, AR170: 15, AR193: 15, AR180: 15, AR165: 14, AR269: 14, AR192:14, AR204: 14, AR164: 14, AR166: 14, AR211: 13, AR033: 13, AR168: 13,AR270: 13, AR207: 12, AR175: 12, AR290: 12, AR169: 12, AR089: 12, AR183:12, AR247: 12, AR176: 11, AR171: 11, AR267: 11, AR178: 11, AR162: 11,AR161: 11, AR217: 11, AR163: 10, AR174: 10, AR229: 10, AR291: 10, AR173:10, AR189: 9, AR214: 9, AR266: 9, AR255: 9, AR181: 8, AR196: 8, AR177:8, AR297: 8, AR289: 8, AR299: 8, AR179: 8, AR190: 8, AR191: 8, AR300: 8,AR060: 8, AR182: 8, AR238: 7, AR216: 7, AR215: 7, AR257: 7, AR261: 7,AR262: 7, AR282: 7, AR296: 7, AR185: 7, AR293: 7, AR235: 6, AR295: 6,AR283: 6, AR231: 6, AR055: 6, AR288: 6, AR285: 6, AR287: 6, AR234: 6,AR258: 6, AR237: 5, AR239: 5, AR236: 5, AR256: 5, AR277: 5, AR286: 5,AR228: 5, AR230: 4, AR294: 4, AR226: 4, AR233: 4, AR260: 4, AR232: 4,AR061: 3, AR227: 3, L0648: 2, L0768: 2, L0766: 2, L0748: 2, L0588: 2,H0125: 1, S0468: 1, H0497: 1, H0486: 1, H0744: 1, H0231: 1, H0266: 1,H0202: 1, H0641: 1, S0422: 1, L0638: 1, L0644: 1, L5572: 1, L0662: 1,L0650: 1, L0807: 1, L0657: 1, L0663: 1, L0665: 1, H0519: 1, L0759: 1,S0026: 1 and L0718: 1. 46 HCQBH72 637548 56  31-174 AR055: 2, AR060: 2,AR299: 2, AR089: 2, AR219: 1, AR185: 1, AR039: 1, AR283: 1, AR104: 1,L0520: 4, L0754: 2, H0263: 1, H0272: 1 and H0555: 1. 47 HCQCC96 84506657 782-919 AR252: 46, AR197: 44, AR204: 38, AR195: 35, AR253: 34, AR178:31, AR230: 31, AR254: 31, AR233: 29, AR250: 28, AR180: 28, AR198: 28,AR266: 26, AR243: 26, AR193: 24, AR239: 23, AR061: 23, AR267: 23, AR201:23, AR227: 22, AR229: 22, AR228: 22, AR237: 21, AR162: 21, AR181: 21,AR163: 21, AR170: 21, AR161: 20, AR257: 20, AR192: 20, AR226: 20, AR176:19, AR234: 19, AR171: 18, AR183: 18, AR245: 18, AR271: 18, AR182: 17,AR258: 17, AR270: 17, AR179: 17, AR275: 17, AR238: 16, AR231: 16, AR296:16, AR261: 16, AR033: 16, AR174: 15, AR185: 15, AR255: 15, AR164: 15,AR262: 15, AR207: 15, AR053: 15, AR165: 15, AR272: 14, AR256: 14, AR039:14, AR269: 14, AR242: 14, AR166: 14, AR205: 14, AR175: 14, AR246: 14,AR300: 13, AR203: 13, AR289: 12, AR236: 12, AR104: 12, AR316: 11, AR232:11, AR293: 11, AR055: 11, AR287: 11, AR169: 11, AR260: 11, AR235: 11,AR168: 11, AR089: 11, AR173: 10, AR308: 10, AR286: 10, AR268: 10, AR291:10, AR060: 10, AR297: 10, AR313: 10, AR288: 10, AR212: 10, AR213: 10,AR299: 10, AR177: 10, AR188: 9, AR096: 9, AR190: 9, AR191: 9, AR294: 9,AR282: 9, AR285: 9, AR283: 9, AR172: 8, AR277: 8, AR189: 8, AR247: 8,AR309: 8, AR312: 8, AR274: 8, AR240: 7, AR218: 7, AR264: 7, AR210: 6,AR200: 6, AR295: 6, AR290: 6, AR219: 6, AR215: 6, AR199: 5, AR263: 5,AR196: 5, AR223: 5, AR311: 5, AR216: 5, AR214: 4, AR224: 4, AR225: 4,AR211: 4, AR217: 4, AR221: 2, AR222: 2, S0360: 5, L0748: 5, L0766: 3,H0657: 2, L3388: 2, H0581: 2, H0596: 2, H0563: 2, S0003: 2, H0328: 2,H0670: 2, L0756: 2, S0436: 2, S0026: 2, H0170: 1, H0556: 1, H0344: 1,H0650: 1, H0656: 1, H0638: 1, S0420: 1, H0675: 1, S0007: 1, H0574: 1,H0632: 1, H0013: 1, H0036: 1, S0010: 1, H0318: 1, H0052: 1, H0251: 1,H0150: 1, H0050: 1, H0090: 1, H0038: 1, S0440: 1, H0130: 1, S0142: 1,S0422: 1, H0529: 1, L0803: 1, L0659: 1, L5623: 1, L0666: 1, S0428: 1,S0126: 1, H0689: 1, H0648: 1, H0672: 1, S0330: 1, H0539: 1, S0378: 1,H0521: 1, H0522: 1, H0478: 1, L0744: 1, L0754: 1, L0779: 1, L0752: 1,S0260: 1, H0445: 1, H0343: 1, H0595: 1, S0434: 1, H0423: 1 and S0424: 1.48 HCUCF89 637986 58 189-278 AR313: 26, AR039: 18, AR277: 13, AR299: 12,AR096: 11, AR089: 11, AR185: 11, AR300: 10, AR240: 8, AR316: 8, AR218:5, AR282: 4, AR104: 4, AR060: 4, AR219: 3, AR055: 2, H0306: 1, L0761: 1and H0436: 1. 49 HCUCK44 790277 59 598-780 AR172: 3, AR245: 3, AR252: 3,AR161: 3, AR164: 3, AR166: 3, AR221: 2, AR162: 2, AR163: 2, AR169: 2,AR311: 2, AR261: 2, AR165: 2, AR214: 2, AR224: 2, AR296: 2, AR264: 1,AR195: 1, AR277: 1, AR212: 1, AR217: 1, AR096: 1, AR193: 1, AR295: 1,AR287: 1, AR216: 1, AR213: 1, AR257: 1, AR275: 1, AR089: 1, AR201: 1,AR282: 1, L3450: 19, H0271: 18, S0002: 12, L0794: 12, S0144: 8, L3783:8, L3807: 8, H0250: 7, L0777: 7, L3119: 6, L3729: 6, L0665: 6, H0518: 6,S0132: 5, H0264: 5, S0426: 5, S0328: 5, S0330: 5, L0758: 5, S0444: 4,S0344: 4, L0770: 4, L0776: 4, L0659: 4, S0052: 4, S0053: 4, L0743: 4,L0747: 4, S0436: 4, L0065: 3, L0769: 3, L0766: 3, L0774: 3, L0657: 3,H0521: 3, L0748: 3, L0749: 3, L0731: 3, L2999: 2, H0306: 2, H0402: 2,H0638: 2, S0360: 2, S0408: 2, S0476: 2, H0393: 2, S0278: 2, L3516: 2,H0050: 2, H0014: 2, H0416: 2, H0617: 2, H0634: 2, H0494: 2, S0440: 2,L0800: 2, L0771: 2, L0648: 2, L0549: 2, L0806: 2, L0805: 2, L0666: 2,S0428: 2, S0216: 2, L3210: 2, S0404: 2, L0439: 2, L0740: 2, L0750: 2,L0752: 2, L0596: 2, L0599: 2, T0002: 1, H0159: 1, H0650: 1, H0657: 1,L0785: 1, H0662: 1, L3659: 1, S0442: 1, S0358: 1, S0410: 1, L3646: 1,H0741: 1, L3117: 1, H0619: 1, L2791: 1, H0613: 1, H0600: 1, H0592: 1,H0486: 1, L2504: 1, L3750: 1, H0069: 1, H0581: 1, H0596: 1, H0044: 1,H0009: 1, H0024: 1, H0057: 1, S0051: 1, H0355: 1, H0615: 1, L0483: 1,S0036: 1, H0090: 1, H0038: 1, H0087: 1, H0413: 1, H0100: 1, S0448: 1,S0142: 1, S0210: 1, H0529: 1, L3904: 1, L0761: 1, L0772: 1, L0372: 1,L0646: 1, L0645: 1, L0764: 1, L0773: 1, L0662: 1, L0768: 1, L0387: 1,L0649: 1, L0551: 1, L0550: 1, L0803: 1, L0775: 1, L0653: 1, L0655: 1,L0656: 1, L0782: 1, L0787: 1, L4537: 1, L2257: 1, S0374: 1, H0690: 1,H0659: 1, H0658: 1, S0378: 1, H0710: 1, S0152: 1, H0696: 1, H0704: 1,S0406: 1, H0436: 1, L0744: 1, L0756: 1, L0779: 1, L0780: 1, L0755: 1,L0759: 1, S0031: 1, L0581: 1, L0601: 1, L0603: 1, S0196: 1, L3632: 1 andH0352: 1. 50 HCUDD64 835082 60 256-402 AR282: 3, AR219: 3, H0052: 3,S3012: 2, L0754: 2, H0402: 1, H0413: 1, S0374: 1, L0438: 1, L0748: 1 andL0740: 1. 51 HCWAE64 535893 61 410-427 AR277: 7, AR282: 1, H0305: 1 52HDPDI72 897277 62  23-385 AR263: 7, AR039: 6, AR089: 5, AR184: 5, AR096:4, AR313: 4, AR299: 4, AR282: 3, AR277: 3, AR240: 3, AR060: 3, AR218: 3,AR249: 3, AR316: 3, AR185: 2, AR055: 2, AR274: 2, AR104: 2, AR267: 2,AR247: 2, AR300: 2, AR206: 1, AR283: 1, AR052: 1, AR312: 1, AR275: 1,AR183: 1, AR270: 1, AR309: 1, AR238: 1, H0521: 2 and H0580: 1. 53HDPGE24 801947 63 173-394 H0555: 8, S0002: 7, L0748: 6, H0556: 5, H0179:5, L0369: 5, S0222: 4, S0474: 4, S0045: 3, H0427: 3, H0599: 3, H0575: 3,H0271: 3, H0628: 3, H0598: 3, S0426: 3, L0766: 3, L0581: 3, H0265: 2,S0114: 2, S0212: 2, H0402: 2, S0442: 2, S0354: 2, S0132: 2, H0431: 2,H0370: 2, H0632: 2, H0581: 2, H0196: 2, H0050: 2, H0124: 2, L0665: 2,H0521: 2, S0390: 2, S0028: 2, L0777: 2, H0444: 2, S0436: 2, H0423: 2,L3643: 1, S0040: 1, L0002: 1, H0381: 1, S0116: 1, H0255: 1, H0662: 1,S0360: 1, H0676: 1, H0580: 1, H0729: 1, H0722: 1, H0728: 1, S0046: 1,H0749: 1, S0300: 1, L0717: 1, L3388: 1, H0586: 1, H0333: 1, H0486: 1,H0706: 1, H0036: 1, T0048: 1, H0318: 1, H0251: 1, H0309: 1, H0121: 1,H0544: 1, S0050: 1, H0375: 1, H0266: 1, S0003: 1, S0214: 1, H0252: 1,H0031: 1, H0644: 1, H0708: 1, H0400: 1, H0063: 1, H0264: 1, S0038: 1,H0280: 1, H0334: 1, H0625: 1, S0440: 1, H0509: 1, H0132: 1, S0210: 1,L0803: 1, L0525: 1, L0555: 1, L0529: 1, L0367: 1, L0532: 1, S0052: 1,S0428: 1, S0216: 1, H0547: 1, H0519: 1, S0126: 1, H0134: 1, S0406: 1,H0727: 1, H0345: 1, S0037: 1, L0740: 1, L0749: 1, S0031: 1, H0445: 1,H0707: 1, L0605: 1, L0604: 1, L0601: 1 and H0543: 1. 54 HDPIU94 81335264 208-279 AR055: 17, AR277: 13, AR060: 12, AR316: 9, AR219: 8, AR240:8, AR089: 8, AR300: 8, AR218: 8, AR039: 7, AR283: 7, AR096: 6, AR282: 5,AR104: 5, AR185: 4, AR299: 4, AR313: 2, L0748: 6, L0666: 5, L0665: 5,L0768: 4, L0777: 4, L0595: 4, H0352: 4, S0045: 3, H0124: 3, L0774: 3,S0028: 3, L0439: 3, L0756: 3, L0592: 3, S0376: 2, S0360: 2, H0619: 2,S0222: 2, L3816: 2, H0635: 2, H0036: 2, H0052: 2, H0046: 2, L0041: 2,S0312: 2, H0551: 2, L3815: 2, L0764: 2, L0663: 2, H0144: 2, L3825: 2,L0751: 2, L0754: 2, L0745: 2, L0731: 2, L0589: 2, H0653: 2, H0136: 2,H0216: 2, H0624: 1, S6024: 1, S0430: 1, H0656: 1, H0255: 1, S0046: 1,H0747: 1, H0645: 1, L2759: 1, H0013: 1, H0156: 1, H0575: 1, H0050: 1,S0050: 1, H0373: 1, H0687: 1, S0314: 1, S0250: 1, H0031: 1, H0135: 1,H0634: 1, H0616: 1, H0380: 1, H0264: 1, H0433: 1, H0059: 1, L0351: 1,S0422: 1, L0800: 1, L0662: 1, L0626: 1, L0766: 1, L0803: 1, L0375: 1,L0655: 1, L0659: 1, L0783: 1, L0809: 1, L0664: 1, L2263: 1, L2258: 1,L2259: 1, H0726: 1, L3826: 1, L3827: 1, H0648: 1, S0152: 1, L3833: 1,H0521: 1, S0390: 1, S3014: 1, S0027: 1, L0749: 1, L0750: 1, L0780: 1,L0758: 1, L0759: 1, S0260: 1 and L0366: 1. 55 HDPIY31 886159 65 268-375AR214: 26, AR263: 25, AR224: 21, AR222: 20, AR264: 20, AR223: 19, AR169:18, AR221: 18, AR217: 18, AR171: 17, AR172: 17, AR195: 17, AR207: 16,AR170: 16, AR311: 16, AR235: 16, AR215: 16, AR225: 16, AR168: 15, AR216:15, AR165: 14, AR197: 14, AR164: 14, AR162: 14, AR308: 13, AR089: 13,AR161: 13, AR166: 13, AR212: 13, AR192: 13, AR193: 13, AR163: 13, AR213:12, AR033: 12, AR309: 12, AR242: 12, AR053: 11, AR245: 11, AR312: 11,AR210: 10, AR282: 10, AR253: 10, AR261: 10, AR254: 10, AR277: 10, AR198:10, AR104: 10, AR295: 10, AR288: 9, AR240: 9, AR316: 9, AR299: 9, AR219:9, AR196: 9, AR205: 9, AR271: 9, AR252: 9, AR285: 9, AR250: 9, AR297: 9,AR272: 8, AR060: 8, AR096: 8, AR177: 8, AR269: 8, AR274: 8, AR246: 8,AR313: 8, AR236: 8, AR211: 8, AR185: 8, AR286: 8, AR039: 7, AR291: 7,AR287: 7, AR275: 7, AR200: 7, AR300: 7, AR055: 7, AR229: 7, AR181: 7,AR283: 7, AR189: 7, AR218: 7, AR175: 7, AR174: 7, AR247: 7, AR238: 7,AR199: 6, AR289: 6, AR188: 6, AR293: 6, AR243: 6, AR191: 6, AR173: 6,AR266: 6, AR262: 6, AR204: 6, AR270: 6, AR226: 6, AR258: 6, AR201: 6,AR176: 6, AR268: 5, AR296: 5, AR257: 5, AR183: 5, AR182: 5, AR234: 5,AR231: 5, AR180: 5, AR255: 5, AR230: 5, AR178: 5, AR256: 5, AR290: 5,AR190: 5, AR239: 5, AR232: 5, AR260: 4, AR227: 4, AR203: 4, AR294: 4,AR267: 4, AR061: 4, AR179: 4, AR237: 4, AR233: 3, AR228: 3, L0439: 56,L0438: 20, H0556: 7, H0052: 7, L0776: 5, S0222: 4, H0438: 4, S0418: 3,S0278: 3, L0770: 3, L0771: 3, L0743: 3, L0366: 3, H0265: 2, S0040: 2,L0415: 2, S0045: 2, H0619: 2, H0492: 2, H0486: 2, H0581: 2, H0620: 2,H0266: 2, H0604: 2, H0031: 2, H0100: 2, L0351: 2, H0144: 2, L0352: 2,H0672: 2, H0521: 2, L0756: 2, L0777: 2, L0731: 2, H0624: 1, H0140: 1,H0583: 1, H0255: 1, H0402: 1, H0305: 1, H0458: 1, S0420: 1, S0354: 1,S0358: 1, H0645: 1, S6022: 1, H0392: 1, H0643: 1, H0559: 1, H0013: 1,H0069: 1, H0156: 1, H0590: 1, S0346: 1, H0085: 1, H0544: 1, H0545: 1,H0439: 1, H0150: 1, H0041: 1, S0388: 1, S0051: 1, T0010: 1, H0271: 1,H0416: 1, H0188: 1, H0288: 1, S0022: 1, T0006: 1, H0213: 1, H0628: 1,H0617: 1, H0135: 1, H0087: 1, H0551: 1, H0477: 1, H0059: 1, S0038: 1,L0435: 1, T0042: 1, H0494: 1, S0344: 1, S0426: 1, L0640: 1, L0769: 1,L0638: 1, L0761: 1, L0642: 1, L0764: 1, L0768: 1, L0794: 1, L0803: 1,L0375: 1, L0806: 1, L0805: 1, L0655: 1, L0659: 1, L0809: 1, L0789: 1,L0665: 1, H0519: 1, S0126: 1, H0690: 1, H0682: 1, S0330: 1, H0539: 1,H0522: 1, S0037: 1, L0751: 1, L0754: 1, L0746: 1, L0749: 1, L0786: 1,L0779: 1, H0445: 1, L0596: 1, H0542: 1 and H0543: 1. 56 HDPOC24 77749366 418-819 H0585: 26, H0141: 12, L0666: 9, L0754: 9, L0755: 9, S0212: 6,L0663: 5, L0743: 5, S0356: 4, H0587: 4, H0553: 4, L0657: 4, L0382: 4,L0740: 4, L0747: 4, S0045: 3, S0046: 3, H0024: 3, L0771: 3, L0648: 3,L0662: 3, L0659: 3, L0664: 3, S0126: 3, H0522: 3, L0748: 3, L0777: 3,L0757: 3, S0192: 3, S0040: 2, S0420: 2, S0442: 2, S0358: 2, S0476: 2,H0550: 2, H0497: 2, H0250: 2, H0575: 2, H0052: 2, H0546: 2, H0266: 2,H0100: 2, H0646: 2, S0002: 2, L0763: 2, L0649: 2, L0803: 2, L0775: 2,L0653: 2, L0517: 2, L0809: 2, L0790: 2, L0665: 2, H0660: 2, S0380: 2,H0521: 2, S3014: 2, S0028: 2, L0751: 2, S0436: 2, H0665: 2, S0430: 1,H0341: 1, S0282: 1, H0664: 1, S0418: 1, S0354: 1, S0444: 1, H0549: 1,S0222: 1, H0600: 1, H0333: 1, H0618: 1, H0253: 1, S0474: 1, H0581: 1,H0235: 1, H0597: 1, H0545: 1, H0009: 1, H0081: 1, H0620: 1, H0023: 1,H0687: 1, S0250: 1, L0483: 1, T0006: 1, L0055: 1, H0087: 1, H0551: 1,H0379: 1, H0264: 1, H0494: 1, H0625: 1, S0352: 1, H0641: 1, H0529: 1,L0371: 1, L0769: 1, L5575: 1, L3905: 1, L5566: 1, L0772: 1, L0800: 1,L0764: 1, L0773: 1, L0794: 1, L0386: 1, L0378: 1, L0806: 1, L0807: 1,L0792: 1, L0565: 1, S0310: 1, H0519: 1, H0682: 1, H0684: 1, H0670: 1,H0672: 1, S0328: 1, S0330: 1, S0332: 1, H0478: 1, S0432: 1, S3012: 1,S0390: 1, S0206: 1, L0742: 1, L0756: 1, L0779: 1, H0707: 1, S0434: 1,L0596: 1, H0668: 1, S0242: 1, H0506: 1 and H0008: 1. 57 HDPOL37 74537767 189-377 AR283: 17, AR089: 16, AR316: 16, AR096: 16, AR277: 15, AR039:15, AR104: 14, AR313: 12, AR060: 11, AR219: 10, AR282: 9, AR240: 9,AR299: 8, AR055: 8, AR185: 8, AR218: 7, AR244: 5, AR265: 4, AR300: 4,AR310: 2, AR295: 2, AR271: 2, AR298: 1, AR175: 1, AR266: 1, AR291: 1,AR286: 1, AR296: 1, AR309: 1, AR312: 1, AR294: 1, H0618: 2, H0040: 1 andH0522: 1. 58 HDPOO76 838594 68 109-159 AR218: 924, AR096: 917, AR219:813, AR316: 779, AR240: 765, AR089: 547, AR313: 512, AR039: 433, AR299:400, AR104: 348, AR300: 336, AR185: 267, AR060: 243, AR282: 172, AR055:155, AR277: 94, AR283: 93, S0474: 29, L0766: 11, H0521: 10, L0803: 7,L0748: 6, L0717: 5, L0759: 5, S0003: 4, L3832: 4, H0663: 3, H0156: 3,L0598: 3, L0770: 3, L0771: 3, L0804: 3, L2439: 3, H0522: 3, L0731: 3,S0436: 3, H0486: 2, S0426: 2, L0805: 2, L0659: 2, L2260: 2, S0126: 2,S0406: 2, L0749: 2, L0755: 2, L0757: 2, L0758: 2, L0590: 2, S0026: 2,H0716: 1, H0341: 1, S0212: 1, L0481: 1, S0444: 1, S0360: 1, L3649: 1,H0637: 1, H0580: 1, H0734: 1, H0749: 1, L3092: 1, H0619: 1, L3388: 1,H0586: 1, H0574: 1, H0427: 1, L0021: 1, H0575: 1, H0318: 1, H0545: 1,H0024: 1, H0373: 1, H0071: 1, H0179: 1, S0214: 1, H0428: 1, H0674: 1,H0591: 1, H0616: 1, H0488: 1, H0494: 1, S0438: 1, S0440: 1, H0647: 1,S0142: 1, UNKWN: 1, L0369: 1, L0763: 1, L0769: 1, L0646: 1, L0648: 1,L0662: 1, L0650: 1, L0775: 1, L0653: 1, L0776: 1, L0656: 1, L0782: 1,L0809: 1, L0519: 1, S0052: 1, L2657: 1, H0144: 1, L3823: 1, H0520: 1,H0547: 1, H0660: 1, S0380: 1, L0742: 1, L0439: 1, L0750: 1, L0777: 1,S0031: 1, H0445: 1, S0434: 1, H0665: 1, H0667: 1, S0194: 1, S0276: 1 andS0458: 1. 59 HDPPQ30 684292 69 220-336 H0542: 4, S0250: 3, H0521: 3,H0522: 3, H0485: 2, H0486: 1, H0494: 1 and H0543: 1. 60 HDQHM36 85232870 129-275 AR313: 50, AR039: 48, AR277: 28, AR089: 26, AR096: 26, AR300:25, AR185: 23, AR299: 22, AR240: 17, AR316: 17, AR104: 15, AR219: 12,AR282: 12, AR218: 12, AR060: 10, AR055: 6, AR283: 5, H0521: 2 61 HE2CM39553651 71 10-51 AR277: 46, AR283: 32, AR219: 30, AR313: 29, AR218: 25,AR316: 25, AR089: 24, AR299: 23, AR104: 23, AR282: 23, AR055: 21, AR300:20, AR185: 18, AR039: 18, AR096: 17, AR240: 17, AR060: 13, L0759: 4,L0657: 3, L0789: 3, L0439: 3, L0752: 3, L0758: 3, S0360: 2, L0805: 2,L0438: 2, L0750: 2, L0777: 2, H0423: 2, H0171: 1, H0638: 1, H0351: 1,H0178: 1, H0606: 1, L0625: 1, L0769: 1, L0771: 1, L0662: 1, L0794: 1,L0803: 1, L0804: 1, L0650: 1, L0774: 1, L0659: 1, L0809: 1, L0663: 1,H0436: 1, L0748: 1, L0740: 1, H0445: 1, L0604: 1 and H0422: 1. 62HE2PO93 771655 72 770-898 AR219: 19, AR218: 19, AR313: 13, AR299: 13,AR185: 13, AR089: 11, AR055: 10, AR316: 10, AR060: 10, AR300: 9, AR096:8, AR104: 7, AR039: 7, AR240: 6, AR282: 6, AR283: 5, AR277: 3, L0803: 5,L0731: 5, S0422: 4, L2903: 3, S0408: 2, H0040: 2, L0766: 2, L0666: 2,L2657: 2, H0144: 2, H0648: 2, L0748: 2, L0439: 2, L0754: 2, L0779: 2,H0170: 1, H0171: 1, S0114: 1, H0657: 1, L2285: 1, S0354: 1, S0360: 1,H0580: 1, H0742: 1, H0741: 1, H0749: 1, L2777: 1, L0717: 1, H0411: 1,H0431: 1, H0586: 1, H0052: 1, H0596: 1, H0014: 1, S0388: 1, S0051: 1,S0003: 1, H0591: 1, T0042: 1, H0625: 1, H0509: 1, L0598: 1, H0026: 1,L0763: 1, L0639: 1, L0372: 1, L0646: 1, L0641: 1, L0768: 1, L0649: 1,L0651: 1, L0805: 1, L0776: 1, L0635: 1, L0664: 1, L0665: 1, L2264: 1,L2262: 1, S0374: 1, L0438: 1, L0352: 1, H0672: 1, S0380: 1, H0696: 1,H0134: 1, S0406: 1, H0478: 1, L0758: 1, L0759: 1, S0436: 1, S0011: 1 andS0424: 1. 63 HE6FU11 827236 73 145-825 AR089: 8, AR104: 6, AR039: 6,AR096: 5, AR060: 5, AR313: 5, AR185: 5, AR055: 4, AR284: 4, AR266: 4,AR316: 4, AR282: 4, AR292: 4, AR299: 4, AR202: 4, AR218: 3, AR289: 3,AR283: 3, AR298: 3, AR277: 3, AR182: 3, AR184: 3, AR280: 3, AR250: 3,AR219: 3, AR315: 3, AR281: 3, AR300: 3, AR169: 3, AR294: 3, AR240: 3,AR291: 3, AR268: 2, AR172: 2, AR033: 2, AR270: 2, AR248: 2, AR310: 2,AR175: 2, AR238: 2, AR241: 2, AR265: 2, AR232: 2, AR285: 2, AR183: 2,AR177: 2, AR227: 2, AR269: 2, AR263: 2, AR290: 2, AR288: 2, AR293: 2,AR229: 2, AR267: 2, AR061: 2, AR176: 2, AR257: 2, AR271: 2, AR296: 2,AR286: 2, AR272: 2, AR259: 1, AR206: 1, AR256: 1, AR214: 1, AR231: 1,AR247: 1, AR295: 1, AR204: 1, AR237: 1, AR226: 1, AR234: 1, AR308: 1,AR253: 1, AR053: 1, AR311: 1, AR205: 1, AR243: 1, AR233: 1, AR173: 1,AR312: 1, AR251: 1, AR314: 1, L0759: 2, H0706: 1, H0123: 1, H0024: 1,H0100: 1, L0794: 1 and L0789: 1. 64 HE6FV29 588454 74 210-311 AR219: 37,AR218: 36, AR315: 34, AR280: 34, AR271: 33, AR244: 29, AR089: 29, AR314:29, AR243: 28, AR281: 26, AR282: 25, AR273: 25, AR205: 24, AR192: 22,AR206: 22, AR198: 19, AR247: 19, AR316: 19, AR039: 19, AR231: 18, AR269:17, AR246: 17, AR204: 16, AR234: 16, AR299: 16, AR313: 15, AR194: 15,AR055: 14, AR186: 14, AR237: 14, AR060: 14, AR241: 13, AR270: 13, AR293:12, AR240: 12, AR232: 11, AR238: 11, AR251: 10, AR300: 10, AR061: 10,AR233: 10, AR227: 10, AR291: 9, AR185: 9, AR202: 9, AR266: 9, AR226: 9,AR229: 9, AR184: 8, AR179: 8, AR182: 8, AR175: 8, AR312: 8, AR268: 8,AR289: 7, AR284: 7, AR249: 7, AR183: 7, AR310: 7, AR267: 7, AR052: 7,AR033: 7, AR296: 7, AR290: 7, AR265: 7, AR177: 7, AR309: 7, AR292: 6,AR298: 6, AR275: 6, AR277: 6, AR285: 6, AR294: 5, AR248: 5, AR053: 5,AR253: 5, AR295: 5, AR286: 5, AR259: 5, AR274: 4, AR258: 4, AR213: 4,AR096: 4, AR256: 4, AR104: 4, AR283: 3, AR263: 2, S0440: 32, S0476: 22,H0494: 20, L0754: 17, S0372: 16, S0132: 13, L0666: 13, S0330: 13, H0046:12, H0586: 11, H0587: 11, S0328: 11, S0360: 10, S0436: 9, S0356: 8,H0622: 8, S0003: 7, L0806: 7, H0648: 7, L0747: 7, L0752: 7, H0674: 6,L0777: 6, L0362: 6, L0662: 5, L0659: 5, L0601: 5, S0430: 4, S0358: 4,S0408: 4, H0592: 4, S0214: 4, H0039: 4, H0031: 4, H0551: 4, H0264: 4,H0560: 4, L0763: 4, L0653: 4, L5623: 4, L0663: 4, S0376: 3, S0444: 3,S0410: 3, H0370: 3, H0600: 3, H0644: 3, L0646: 3, L0649: 3, L0776: 3,L0783: 3, L0809: 3, L0665: 3, H0696: 3, S0406: 3, S3014: 3, L0755: 3,S0434: 3, L0591: 3, H0170: 2, S0134: 2, H0662: 2, S0442: 2, H0393: 2,H0596: 2, H0597: 2, H0688: 2, H0553: 2, H0032: 2, H0169: 2, H0598: 2,H0090: 2, H0379: 2, H0380: 2, L0770: 2, L0372: 2, L0549: 2, L0376: 2,L0517: 2, L0518: 2, L5622: 2, H0658: 2, H0670: 2, S0380: 2, S0152: 2,S0350: 2, S0027: 2, L0744: 2, L0779: 2, L0759: 2, L0599: 2, S0196: 2,S0456: 2, H0171: 1, H0556: 1, T0002: 1, H0713: 1, H0483: 1, H0663: 1,L0005: 1, S0354: 1, T0008: 1, H0742: 1, H0741: 1, H0411: 1, H0549: 1,T0039: 1, H0013: 1, L0021: 1, H0349: 1, S0010: 1, H0204: 1, L0738: 1,H0545: 1, H0014: 1, H0015: 1, H0373: 1, H0355: 1, H0510: 1, H0615: 1,L0483: 1, L0142: 1, L0143: 1, H0166: 1, H0673: 1, H0708: 1, H0591: 1,H0038: 1, H0040: 1, H0634: 1, T0067: 1, H0272: 1, H0487: 1, H0412: 1,H0623: 1, H0059: 1, H0100: 1, S0352: 1, S0382: 1, S0448: 1, S0306: 1,S0438: 1, S0472: 1, H0646: 1, L0503: 1, L0640: 1, L0637: 1, L0761: 1,L0772: 1, L0764: 1, L0771: 1, L0648: 1, L0794: 1, L5564: 1, L0551: 1,L0805: 1, L0382: 1, L0519: 1, L0789: 1, L0532: 1, L0664: 1, H0144: 1,H0520: 1, H0547: 1, S0126: 1, H0689: 1, H0711: 1, H0435: 1, H0659: 1,H0666: 1, S0378: 1, H0704: 1, S0044: 1, H0555: 1, S0392: 1, S0322: 1,L0748: 1, L0740: 1, L0745: 1, L0749: 1, L0756: 1, L0757: 1 and S0242: 1.65 HE9EA10 827796 75 212-448 L0794: 12, H0620: 3, L0756: 2, L0759: 2,S0408: 1, S0049: 1, H0544: 1, H0012: 1, H0615: 1, H0040: 1, L0764: 1,L0803: 1, L0806: 1, L0789: 1, H0144: 1, H0547: 1, L0779: 1, L0597: 1 andL0595: 1. 66 HEBCY54 600355 76 172-528 AR104: 9, AR277: 6, AR283: 5,AR055: 4, AR096: 4, AR060: 4, AR240: 4, AR282: 2, AR316: 2, AR185: 2,AR300: 2, AR299: 2, AR089: 2, AR039: 2, AR313: 1, AR218: 1, L0438: 3,L0748: 3, T0010: 2, L0351: 2, L0769: 2, H0521: 2, L0439: 2, L0747: 2,S0116: 1, S0354: 1, S0007: 1, H0619: 1, H0253: 1, H0565: 1, H0135: 1,L0641: 1, L0521: 1, L0774: 1, L0809: 1, L0789: 1, H0520: 1, L0755: 1,L0758: 1 and H0445: 1. 67 HEBDF77 692347 77 681-791 AR104: 10, AR213: 5,AR055: 4, AR172: 4, AR060: 4, AR221: 4, AR254: 3, AR161: 3, AR162: 3,AR170: 3, AR089: 3, AR163: 3, AR207: 3, AR218: 3, AR313: 3, AR039: 2,AR223: 2, AR096: 2, AR205: 2, AR296: 2, AR185: 2, AR282: 2, AR243: 2,AR283: 2, AR230: 2, AR181: 2, AR197: 2, AR299: 2, AR224: 2, AR316: 2,AR228: 2, AR300: 2, AR176: 2, AR277: 1, AR295: 1, AR217: 1, AR219: 1,AR309: 1, AR222: 1, AR240: 1, AR238: 1, AR216: 1, AR226: 1, AR233: 1,AR264: 1, AR177: 1, AR266: 1, AR289: 1, AR297: 1, L0805: 6, L0438: 5,L0439: 5, L0794: 3, L0759: 2, L0005: 1, S0007: 1, H0351: 1, S0346: 1,L0157: 1, L0351: 1, L0769: 1, L0638: 1, L0776: 1, L0741: 1, L0756: 1,L0608: 1 and L0366: 1. 68 HEBDQ91 840288 78 1211-1336 AR218: 18, AR219:15, AR104: 14, AR185: 11, AR055: 10, AR060: 9, AR313: 9, AR299: 8,AR096: 7, AR089: 7, AR282: 7, AR316: 6, AR240: 6, AR277: 6, AR283: 6,AR039: 5, AR300: 5 S0007: 5, L0805: 3, S6026: 1, L0769: 1, L0438: 1,L0741: 1, L0748: 1 and L0758: 1. 69 HEBFR46 847064 79 200-289 AR313: 58,AR039: 47, AR300: 30, AR096: 29, AR299: 29, AR277: 28, AR089: 27, AR185:27, AR316: 22, AR219: 22, AR104: 21, AR218: 20, AR240: 20, AR282: 15,AR060: 15, AR055: 11, AR283: 7, H0457: 10, H0550: 5, H0436: 5, H0549: 4,H0616: 4, L0519: 4, H0556: 3, H0580: 3, S0007: 3, S0046: 3, L0809: 3,L0747: 3, L0777: 3, S0436: 3, H0295: 2, T0040: 2, H0266: 2, L0761: 2,L0783: 2, L0789: 2, H0658: 2, H0521: 2, L0753: 2, L0731: 2, L0596: 2,H0543: 2, S0040: 1, S0116: 1, S0282: 1, H0662: 1, H0402: 1, H0125: 1,L0534: 1, L0562: 1, S0356: 1, S0358: 1, H0749: 1, L3816: 1, H0559: 1,H0069: 1, H0599: 1, H0618: 1, H0253: 1, H0581: 1, H0546: 1, H0123: 1,S0051: 1, H0083: 1, H0687: 1, H0284: 1, H0124: 1, H0038: 1, H0551: 1,H0623: 1, S0038: 1, T0041: 1, S0440: 1, S0150: 1, L3818: 1, S0002: 1,L0763: 1, L0769: 1, L5575: 1, L0627: 1, L0800: 1, L0662: 1, L0803: 1,L0793: 1, L0666: 1, L2264: 1, L3825: 1, L3827: 1, L3828: 1, H0547: 1,H0519: 1, H0539: 1, S0037: 1, S0206: 1, L0748: 1, L0749: 1, H0595: 1,L0593: 1, S0194: 1 and S0276: 1. 70 HEBGE07 798096 80 106-234 S0007: 171 HEGAU15 834379 81  59-163 AR299: 9, AR039: 8, AR300: 8, AR055: 7,AR240: 7, AR060: 7, AR313: 6, AR282: 6, AR277: 6, AR104: 5, AR089: 5,AR096: 5, AR185: 5, AR316: 4, AR283: 4, AR218: 4, AR219: 3, H0550: 2,L0749: 2, H0318: 1 and H0555: 1. 72 HEQBF89 786205 82 306-458 AR313: 76,AR277: 64, AR039: 62, AR299: 47, AR089: 47, AR316: 44, AR096: 43, AR185:41, AR300: 40, AR283: 38, AR282: 37, AR104: 34, AR240: 34, AR219: 33,AR218: 29, AR055: 22, AR060: 21, H0544: 1 73 HFCEI04 692438 83 136-264AR055: 7, AR060: 7, AR104: 6, AR240: 6, AR282: 6, AR218: 5, AR185: 5,AR283: 5, AR089: 4, AR300: 4, AR313: 3, AR299: 3, AR316: 3, AR096: 3,AR039: 3, AR277: 3, AR219: 2, H0009: 3 74 HFEAY59 658685 84 154-276AR055: 5, AR277: 5, AR283: 5, AR060: 4, AR282: 4, AR104: 4, AR300: 3,AR240: 3, AR316: 2, AR039: 2, AR089: 2, AR096: 2, AR218: 2, AR185: 2,AR219: 1, AR299: 1, H0081: 2 and H0586: 1. 75 HFIJA68 847074 85 283-414AR241: 47, AR313: 34, AR039: 26, AR089: 24, AR198: 24, AR192: 23, AR204:18, AR183: 17, AR299: 16, AR229: 16, AR218: 16, AR096: 15, AR185: 15,AR300: 14, AR271: 14, AR275: 14, AR240: 13, AR247: 13, AR243: 12, AR238:12, AR194: 12, AR316: 12, AR258: 12, AR226: 12, AR219: 11, AR177: 11,AR293: 11, AR274: 10, AR175: 10, AR273: 10, AR277: 10, AR233: 9, AR312:9, AR280: 9, AR234: 9, AR104: 9, AR315: 9, AR292: 8, AR269: 8, AR231: 8,AR205: 8, AR314: 7, AR060: 7, AR295: 7, AR265: 7, AR237: 7, AR053: 7,AR179: 7, AR186: 7, AR270: 7, AR281: 7, AR052: 7, AR267: 6, AR268: 6,AR227: 6, AR294: 6, AR249: 6, AR202: 6, AR033: 6, AR182: 6, AR184: 6,AR246: 6, AR259: 6, AR256: 5, AR213: 5, AR282: 5, AR232: 4, AR206: 4,AR309: 4, AR253: 4, AR310: 4, AR296: 4, AR251: 4, AR055: 3, AR290: 3,AR248: 3, AR291: 3, AR286: 3, AR285: 2, AR298: 2, AR263: 2, AR289: 2,AR061: 2, AR244: 2, AR284: 2, AR283: 2, AR266: 1, S0194: 1 76 HFKEU12634006 86  6-173 AR055: 9, AR219: 7, AR060: 7, AR282: 6, AR277: 5,AR039: 5, AR104: 5, AR313: 5, AR300: 5, AR218: 4, AR299: 4, AR283: 4,AR240: 4, AR089: 4, AR316: 4, AR096: 3, AR185: 3, H0012: 2 and L0805: 1.77 HFPCZ55 840840 87 676-810 L0756: 6, L0439: 4, L0777: 4, L0662: 3,H0672: 3, S0358: 2, L0659: 2, L0666: 2, S0031: 2, S0360: 1, H0411: 1,H0369: 1, S0222: 1, S0220: 1, S0005: 1, H0575: 1, T0082: 1, H0050: 1,S6028: 1, H0169: 1, H0100: 1, L0769: 1, L0774: 1, L0776: 1, L0647: 1,L0663: 1, H0660: 1, H0651: 1, S0146: 1, L0743: 1, L0757: 1, L0361: 1 andL0462: 1. 78 HFTBM38 638338 88 577-669 AR185: 7, AR089: 5, AR055: 5,AR104: 4, AR218: 3, AR060: 3, AR299: 3, AR316: 3, AR277: 3, AR300: 2,AR240: 2, AR282: 2, AR039: 2, AR096: 2, AR313: 2, AR283: 1, AR219: 1,L0439: 14, H0052: 9, L0770: 3, H0544: 2, L0769: 2, L0650: 2, L0438: 2,H0593: 2, L0742: 2, L0779: 2, L0758: 2, S0040: 1, H0581: 1, H0009: 1,H0567: 1, H0566: 1, H0123: 1, H0266: 1, H0687: 1, H0433: 1, H0100: 1,S0002: 1, L0369: 1, L0640: 1, L0639: 1, L0637: 1, L5575: 1, L5565: 1,L0764: 1, L0521: 1, L0794: 1, L0803: 1, L0653: 1, L0655: 1, L0647: 1,L0367: 1, L5623: 1, L0790: 1, L0663: 1, L0665: 1, H0670: 1, S0406: 1,H0479: 1, L0743: 1, L0751: 1, L0747: 1, L0749: 1, L0757: 1, S0434: 1,H0665: 1 and H0352: 1. 79 HFTDH56 862021 89 67-99 AR060: 10, AR096: 9,AR055: 9, AR104: 8, AR240: 6, AR218: 6, AR283: 5, AR185: 5, AR089: 5,AR300: 4, AR316: 4, AR299: 4, AR219: 3, AR277: 3, AR282: 3, AR039: 2,AR313: 2, L0754: 7, L0777: 6, L0794: 4, L0803: 4, L0750: 4, L0731: 4,H0046: 3, H0050: 3, H0620: 3, H0135: 3, H0539: 3, L0749: 3, L0759: 3,H0550: 2, T0039: 2, H0013: 2, H0052: 2, H0039: 2, L0809: 2, H0547: 2,L0748: 2, H0624: 1, S0001: 1, H0208: 1, H0619: 1, H0393: 1, S0278: 1,H0069: 1, H0635: 1, H0253: 1, H0123: 1, H0024: 1, T0010: 1, H0687: 1,H0428: 1, H0494: 1, L0764: 1, L0784: 1, L0807: 1, L0438: 1, H0689: 1,L0747: 1 and L0755: 1. 80 HFVHW43 570948 90  92-211 H0393: 1 81 HGBHP91693011 91  50-208 AR313: 32, AR039: 24, AR299: 22, AR089: 21, AR185: 17,AR096: 16, AR060: 15, AR316: 13, AR300: 13, AR277: 13, AR240: 12, AR218:11, AR055: 11, AR104: 11, AR282: 9, AR219: 9, AR283: 5, H0014: 1 82HHEAK45 765278 92 813-824 AR277: 12, AR283: 11, AR313: 11, AR316: 9,AR282: 9, AR089: 7, AR240: 7, AR104: 7, AR299: 7, AR039: 7, AR218: 6,AR096: 6, AR055: 6, AR300: 6, AR185: 6, AR060: 4, AR219: 3, L0758: 9,L0748: 6, L0747: 6, L0779: 5, L0750: 4, H0556: 3, S0440: 3, H0658: 3,H0656: 2, L0770: 2, L0769: 2, L0804: 2, L0774: 2, H0144: 2, H0648: 2,L0439: 2, L0749: 2, L0596: 2, H0265: 1, S0444: 1, H0318: 1, H0597: 1,H0050: 1, H0024: 1, H0135: 1, H0090: 1, H0038: 1, H0616: 1, H0494: 1,L0065: 1, S0422: 1, H0529: 1, L0637: 1, L0764: 1, L0768: 1, L0794: 1,L0387: 1, L0803: 1, L0805: 1, L0809: 1, L0788: 1, L0790: 1, L0664: 1,L0438: 1, H0555: 1, L0780: 1, L0731: 1, H0444: 1, H0542: 1, H0543: 1 andH0423: 1. 83 HHEGS55 858372 93 159-269 AR039: 82, AR313: 78, AR300: 45,AR096: 42, AR277: 41, AR185: 40, AR299: 37, AR089: 37, AR104: 29, AR316:28, AR240: 24, AR219: 20, AR218: 19, AR282: 17, AR060: 16, AR055: 8,AR283: 7, H0542: 5 84 HHEOW19 886174 94 183-377 AR169: 30, AR089: 25,AR207: 25, AR308: 25, AR214: 24, AR263: 24, AR165: 24, AR264: 24, AR164:23, AR161: 23, AR168: 23, AR222: 23, AR171: 22, AR283: 22, AR166: 22,AR162: 22, AR311: 21, AR163: 21, AR096: 21, AR223: 21, AR213: 19, AR104:19, AR316: 19, AR219: 19, AR218: 18, AR217: 18, AR312: 18, AR212: 18,AR225: 17, AR309: 17, AR282: 17, AR313: 17, AR039: 17, AR272: 17, AR299:16, AR216: 16, AR060: 15, AR172: 15, AR274: 15, AR053: 15, AR170: 15,AR240: 14, AR055: 14, AR185: 14, AR195: 13, AR277: 13, AR197: 13, AR235:13, AR295: 12, AR192: 12, AR224: 12, AR296: 11, AR297: 11, AR246: 11,AR285: 10, AR198: 10, AR245: 10, AR293: 10, AR252: 10, AR288: 10, AR205:10, AR300: 10, AR221: 9, AR242: 9, AR287: 9, AR201: 9, AR247: 9, AR253:9, AR033: 9, AR266: 9, AR215: 9, AR275: 8, AR291: 8, AR174: 8, AR261: 8,AR193: 8, AR243: 8, AR271: 8, AR177: 8, AR270: 8, AR254: 8, AR289: 7,AR236: 7, AR286: 7, AR175: 6, AR204: 6, AR269: 6, AR189: 6, AR294: 6,AR180: 6, AR178: 5, AR250: 5, AR183: 5, AR199: 5, AR257: 5, AR181: 5,AR179: 5, AR268: 5, AR262: 5, AR173: 5, AR290: 5, AR258: 5, AR255: 4,AR061: 4, AR210: 4, AR191: 4, AR190: 4, AR229: 4, AR196: 4, AR176: 4,AR188: 3, AR226: 3, AR239: 3, AR182: 3, AR200: 3, AR234: 3, AR238: 3,AR267: 3, AR232: 3, AR230: 3, AR203: 3, AR256: 3, AR231: 3, AR211: 3,AR237: 3, AR233: 2, AR227: 2, AR260: 2, AR228: 1, L0748: 4, L0745: 4,L0775: 3, L0776: 3, L0758: 3, H0458: 2, H0050: 2, S0003: 2, H0529: 2,L0764: 2, L0747: 2, L0599: 2, L0362: 2, H0556: 1, S0116: 1, S0282: 1,H0662: 1, H0305: 1, S0420: 1, S0444: 1, H0329: 1, H0351: 1, H0411: 1,S0278: 1, H0438: 1, T0039: 1, H0635: 1, H0156: 1, H0235: 1, H0327: 1,L0471: 1, H0428: 1, H0031: 1, H0644: 1, H0032: 1, S0366: 1, H0038: 1,H0616: 1, T0067: 1, H0477: 1, H0059: 1, H0560: 1, H0625: 1, S0422: 1,L0769: 1, L0761: 1, L0667: 1, L0771: 1, L0662: 1, L0806: 1, L0655: 1,L0809: 1, L5622: 1, L0789: 1, L0790: 1, L0665: 1, S0052: 1, H0144: 1,H0520: 1, H0547: 1, H0519: 1, H0435: 1, H0539: 1, S0044: 1, S0392: 1,L0754: 1, L0749: 1, L0750: 1, L0779: 1, L0755: 1, L0759: 1, S0434: 1,L0608: 1, H0543: 1 and S0452: 1. 85 HHFFL34 753230 95  42-713 AR265: 3,AR183: 3, AR184: 3, AR248: 3, AR309: 2, AR310: 2, AR269: 2, AR206: 1,AR282: 1, AR267: 1, AR270: 1, AR295: 1, AR277: 1, AR186: 1, AR205: 1,H0599: 3, L0766: 3, S0037: 3, H0556: 2, H0242: 2, H0620: 2, H0543: 2,H0170: 1, T0002: 1, H0300: 1, S0360: 1, S0045: 1, S0476: 1, H0549: 1,H0309: 1, H0545: 1, H0081: 1, H0050: 1, S0388: 1, H0644: 1, T0041: 1,S0144: 1, H0529: 1, H0026: 1, L0659: 1, L2261: 1, H0520: 1, S0126: 1,H0539: 1, L0602: 1, S0152: 1, S0044: 1, H0436: 1, S3014: 1, S0027: 1,L0779: 1, L0731: 1 and S0424: 1. 86 HHFFS40 824059 96  37-180 AR219: 22,AR277: 18, AR283: 17, AR218: 16, AR039: 15, AR282: 15, AR089: 14, AR316:13, AR313: 13, AR096: 12, AR299: 12, AR104: 12, AR240: 10, AR055: 10,AR300: 10, AR185: 9, AR060: 8, S0422: 7, L0748: 6, L0591: 6, L0766: 5,L0754: 5, H0423: 5, S0408: 4, H0069: 4, L0803: 4, L0602: 4, H0657: 3,S0442: 3, S0046: 3, H0596: 3, S0003: 3, H0032: 3, H0169: 3, H0674: 3,L0662: 3, L0794: 3, L0526: 3, H0670: 3, L0740: 3, L0759: 3, S0134: 2,S0212: 2, H0661: 2, S0444: 2, H0046: 2, L0471: 2, H0355: 2, H0038: 2,H0100: 2, L0564: 2, S0440: 2, H0529: 2, L0770: 2, L0769: 2, L0667: 2,L0771: 2, L0521: 2, L0804: 2, L0805: 2, L0384: 2, L0809: 2, L0665: 2,H0659: 2, L0743: 2, L0750: 2, L0731: 2, S0436: 2, L0592: 2, L0599: 2,L0608: 2, L0362: 2, H0171: 1, H0556: 1, H0686: 1, H0713: 1, H0717: 1,H0738: 1, H0740: 1, H0656: 1, H0663: 1, H0662: 1, H0402: 1, S0356: 1,H0742: 1, H0730: 1, H0747: 1, S0222: 1, H0574: 1, H0632: 1, H0486: 1,H0013: 1, H0581: 1, S0049: 1, H0052: 1, H0194: 1, H0309: 1, H0263: 1,H0123: 1, H0050: 1, H0373: 1, H0510: 1, S6028: 1, H0266: 1, H0615: 1,L0483: 1, H0644: 1, L0143: 1, H0708: 1, H0135: 1, H0163: 1, H0090: 1,H0616: 1, T0067: 1, H0488: 1, H0412: 1, H0059: 1, H0494: 1, S0382: 1,S0306: 1, S0450: 1, H0509: 1, H0641: 1, H0647: 1, H0646: 1, L0520: 1,L0763: 1, L0637: 1, L0373: 1, L0363: 1, L5564: 1, L0775: 1, L0375: 1,L0651: 1, L0655: 1, L0661: 1, L0527: 1, L0656: 1, L0659: 1, L0518: 1,L0532: 1, L0663: 1, L0664: 1, S0374: 1, H0682: 1, H0658: 1, H0660: 1,H0672: 1, H0539: 1, H0521: 1, S0044: 1, S0406: 1, H0478: 1, L0744: 1,L0439: 1, L0747: 1, L0779: 1, L0777: 1, L0758: 1, L0480: 1, L0595: 1,H0667: 1, S0192: 1, S0194: 1, S0196: 1, H0422: 1 and S0424: 1. 87HHGCS78 634605 97 290-364 AR277: 76, AR283: 71, AR219: 57, AR218: 56,AR316: 56, AR089: 52, AR313: 52, AR240: 51, AR055: 45, AR282: 45, AR299:44, AR104: 41, AR096: 41, AR185: 34, AR039: 33, AR060: 31, AR300: 30,L0770: 7, H0333: 3, L0783: 2, L0731: 2, H0445: 2, S0418: 1, H0741: 1,S0002: 1, L0369: 1, L0643: 1, L0764: 1, L0794: 1, L0803: 1, L0775: 1,L0375: 1, L0378: 1, L0655: 1, L0809: 1, L0666: 1, L0664: 1, L0754: 1,L0747: 1, L0749: 1, L0752: 1 and L0591: 1. 88 HHGDT26 658692 98 181-207L0748: 2, S0218: 1, H0333: 1, H0271: 1, S0210: 1, L0776: 1, S0188: 1,L0745: 1 and H0423: 1. 89 HHPFU28 824573 99 156-239 AR218: 11, AR039: 9,AR219: 9, AR104: 8, AR300: 8, AR185: 7, AR055: 6, AR299: 6, AR089: 6,AR096: 6, AR240: 6, AR060: 5, AR282: 5, AR316: 5, AR313: 4, AR277: 3,AR283: 3, L0622: 2, L0518: 2, L0382: 2, L0663: 2, L0750: 2, L0752: 2,L0362: 2, S0114: 1, S0420: 1, S0354: 1, S0444: 1, S0222: 1, S0010: 1,H0046: 1, H0051: 1, L0483: 1, H0644: 1, H0412: 1, H0529: 1, L0794: 1,L0561: 1, L0666: 1, S0330: 1, S0028: 1, L0779: 1, L0777: 1, L0758: 1,S0031: 1, H0444: 1 and L0592: 1. 90 HHSBI06 639097 100 690-707 AR218:14, AR060: 11, AR282: 11, AR055: 11, AR089: 10, AR219: 10, AR185: 10,AR277: 10, AR039: 9, AR104: 9, AR299: 8, AR316: 8, AR300: 8, AR313: 8,AR283: 7, AR096: 7, AR240: 5, L0766: 12, L0794: 7, L0439: 7, L0749: 7,L0803: 6, L0740: 6, L0745: 6, H0052: 5, L0754: 5, L3181: 4, L0770: 4,L0666: 4, L0748: 4, H0553: 3, L0790: 3, L0589: 3, H0543: 3, S0114: 2,S0134: 2, H0650: 2, S0354: 2, S0444: 2, H0747: 2, S0476: 2, H0393: 2,H0549: 2, H0586: 2, H0013: 2, H0599: 2, H0014: 2, S0051: 2, S0003: 2,H0032: 2, H0674: 2, H0135: 2, S0142: 2, L0372: 2, L0800: 2, L0764: 2,L0805: 2, L0655: 2, L0657: 2, L0659: 2, L0809: 2, L0789: 2, L0792: 2,H0144: 2, L0438: 2, H0684: 2, H0658: 2, H0539: 2, H0521: 2, S0406: 2,S0028: 2, L0750: 2, L0779: 2, L0777: 2, L0752: 2, L0731: 2, L0758: 2,S0436: 2, H0653: 2, H0542: 2, H0556: 1, H0716: 1, H0381: 1, S0116: 1,H0661: 1, S0356: 1, S0442: 1, S0360: 1, H0675: 1, H0734: 1, L2255: 1,L3726: 1, H0261: 1, S0222: 1, L3499: 1, T0114: 1, H0706: 1, H0036: 1,H0318: 1, H0581: 1, L0738: 1, H0123: 1, H0620: 1, S0050: 1, H0015: 1,H0051: 1, H0355: 1, H0416: 1, H0286: 1, H0328: 1, H0428: 1, H0622: 1,T0006: 1, H0030: 1, H0031: 1, H0644: 1, H0617: 1, L0055: 1, H0124: 1,H0163: 1, H0038: 1, H0040: 1, H0616: 1, H0551: 1, H0264: 1, H0102: 1,S0112: 1, L0564: 1, H0280: 1, H0494: 1, H0561: 1, S0440: 1, H0633: 1,L3815: 1, S0002: 1, L0763: 1, L0769: 1, L0761: 1, L0646: 1, L0642: 1,L0644: 1, L0645: 1, L0648: 1, L0662: 1, L0363: 1, L0775: 1, L0375: 1,L0651: 1, L0784: 1, L0806: 1, L0653: 1, L0807: 1, L0658: 1, L0540: 1,L5622: 1, L0368: 1, L0665: 1, L2655: 1, L2257: 1, L2263: 1, L2258: 1,L2262: 1, S0374: 1, H0723: 1, L3811: 1, L2670: 1, H0547: 1, L3215: 1,H0648: 1, H0672: 1, S0328: 1, H0753: 1, H0522: 1, H0436: 1, S0392: 1,H0626: 1, L0759: 1, S0031: 1, H0445: 1, S0434: 1, L0596: 1, L0588: 1,S0192: 1, H0423: 1, S0424: 1 and H0352: 1. 91 HHSBI65 801910 101  62-229AR176: 10, AR216: 9, AR217: 8, AR168: 8, AR169: 8, AR182: 8, AR161: 8,AR196: 8, AR162: 8, AR214: 8, AR228: 8, AR269: 8, AR231: 8, AR233: 7,AR171: 7, AR207: 7, AR229: 7, AR181: 7, AR223: 7, AR163: 7, AR198: 7,AR165: 7, AR172: 7, AR225: 7, AR267: 7, AR224: 7, AR266: 6, AR268: 6,AR170: 6, AR164: 6, AR237: 6, AR221: 6, AR222: 6, AR177: 6, AR179: 6,AR235: 6, AR270: 6, AR183: 6, AR204: 6, AR288: 6, AR053: 6, AR239: 6,AR193: 5, AR236: 5, AR250: 5, AR191: 5, AR264: 5, AR293: 5, AR296: 5,AR055: 5, AR238: 5, AR247: 5, AR309: 5, AR300: 5, AR178: 5, AR295: 5,AR290: 5, AR294: 5, AR060: 5, AR061: 5, AR287: 5, AR257: 5, AR201: 5,AR282: 5, AR291: 5, AR175: 5, AR311: 4, AR261: 4, AR234: 4, AR289: 4,AR275: 4, AR262: 4, AR252: 4, AR242: 4, AR213: 4, AR253: 4, AR297: 4,AR203: 4, AR277: 4, AR180: 4, AR212: 4, AR200: 4, AR316: 4, AR286: 4,AR274: 4, AR255: 4, AR312: 4, AR240: 4, AR174: 4, AR215: 4, AR039: 4,AR192: 4, AR263: 4, AR205: 4, AR283: 3, AR232: 3, AR271: 3, AR285: 3,AR190: 3, AR226: 3, AR185: 3, AR033: 3, AR246: 3, AR230: 3, AR188: 3,AR308: 3, AR227: 3, AR096: 3, AR173: 3, AR313: 3, AR089: 3, AR195: 3,AR272: 3, AR199: 3, AR189: 3, AR260: 3, AR197: 3, AR299: 3, AR104: 2,AR210: 2, AR258: 2, AR211: 2, AR256: 2, AR243: 2, AR218: 2, AR219: 2,L0439: 7, L0794: 5, L0766: 5, S0354: 2, H0549: 2, S0051: 2, S0142: 2,L0372: 2, L0809: 2, L0438: 2, H0658: 2, H0650: 1, H0381: 1, S0116: 1,S0356: 1, S0360: 1, H0261: 1, H0586: 1, H0486: 1, H0036: 1, H0052: 1,L0738: 1, H0457: 1, H0014: 1, H0051: 1, H0617: 1, H0032: 1, H0561: 1,S0440: 1, H0633: 1, L0763: 1, L0761: 1, L0800: 1, L0644: 1, L0645: 1,L0764: 1, L0648: 1, L0655: 1, L0657: 1, L0658: 1, L0368: 1, L0665: 1,L3811: 1, S0044: 1, S0406: 1, H0626: 1, L0731: 1, S0434: 1, S0436: 1,H0653: 1 and H0423: 1. 92 HHSDI53 862028 102 221-295 AR313: 45, AR039:43, AR300: 22, AR299: 22, AR096: 21, AR316: 20, AR185: 19, AR089: 19,AR277: 19, AR219: 15, AR240: 14, AR104: 14, AR218: 13, AR282: 12, AR060:11, AR055: 8, AR283: 4, L0766: 10, L0752: 8, L0439: 6, L0747: 6, L0740:5, L0756: 5, S0408: 4, L0779: 4, L0777: 4, L0731: 4, S0051: 3, H0169: 3,L0803: 3, L0774: 3, L0809: 3, L0754: 3, S0360: 2, H0574: 2, S0422: 2,L0763: 2, L0805: 2, L0666: 2, L0663: 2, L0751: 2, L0755: 2, L0759: 2,L0601: 2, H0624: 1, S0040: 1, H0713: 1, S0114: 1, S0298: 1, S0420: 1,S0444: 1, H0580: 1, H0730: 1, H0733: 1, L3388: 1, H0351: 1, H0600: 1,H0331: 1, H0013: 1, L0021: 1, H0575: 1, H0590: 1, T0110: 1, H0012: 1,H0615: 1, H0031: 1, H0553: 1, H0591: 1, S0440: 1, H0646: 1, S0002: 1,L0772: 1, L0645: 1, L0773: 1, L0662: 1, L0794: 1, L0381: 1, L0775: 1,L0776: 1, L0657: 1, L0659: 1, L0528: 1, L5622: 1, L0790: 1, H0547: 1,H0648: 1, H0539: 1, S0152: 1, H0696: 1, S0044: 1, S0406: 1, S0028: 1,L0758: 1, S0434: 1, S0436: 1, L0366: 1, S0011: 1, S0276: 1, H0422: 1,S0398: 1 and S0424: 1. 93 HISAT67 843549 103 1239-1409 AR283: 20, AR282:15, AR277: 11, AR089: 11, AR219: 11, AR299: 10, AR218: 10, AR316: 9,AR313: 8, AR096: 8, AR185: 8, AR104: 7, AR240: 7, AR055: 6, AR060: 6,AR039: 6, AR300: 6, L0751: 8, L0754: 6, L0731: 6, H0556: 5, L0766: 5,L0439: 5, L0750: 5, L0770: 4, L0666: 4, H0521: 4, S0356: 3, H0052: 3,H0424: 3, L0776: 3, S0406: 3, S0418: 2, S0442: 2, H0580: 2, H0733: 2,H0486: 2, H0575: 2, S0438: 2, L0769: 2, L3905: 2, L0659: 2, L0663: 2,L0665: 2, L0748: 2, L0749: 2, S0436: 2, T0002: 1, H0159: 1, S6024: 1,S0134: 1, H0656: 1, H0484: 1, S0358: 1, S0360: 1, H0742: 1, S0046: 1,H0393: 1, S0278: 1, H0607: 1, H0586: 1, H0642: 1, H0632: 1, H0427: 1,L0021: 1, H0599: 1, H0318: 1, H0746: 1, H0194: 1, L0738: 1, H0178: 1,H0566: 1, H0051: 1, T0010: 1, H0408: 1, H0290: 1, H0328: 1, H0401: 1,H0417: 1, H0553: 1, H0617: 1, H0040: 1, H0264: 1, H0623: 1, H0059: 1,T0041: 1, H0494: 1, H0561: 1, H0509: 1, S0144: 1, L0763: 1, L0638: 1,L5565: 1, L0772: 1, L0373: 1, L0764: 1, L0662: 1, L0626: 1, L0363: 1,L0649: 1, L0650: 1, L0774: 1, L0806: 1, L0654: 1, L0789: 1, L0664: 1,L3822: 1, H0699: 1, S0374: 1, L3828: 1, H0547: 1, H0689: 1, H0659: 1,H0658: 1, H0670: 1, H0672: 1, H0539: 1, L0740: 1, L0746: 1, L0752: 1,L0755: 1, L0757: 1, L0584: 1, L0596: 1, L0608: 1 and H0352: 1. 94HJBCU75 638329 104 61-78 AR162: 12, AR161: 12, AR163: 11, AR186: 10,AR244: 10, AR273: 8, AR222: 8, AR225: 8, AR221: 8, AR214: 8, AR216: 8,AR224: 7, AR223: 7, AR282: 7, AR215: 7, AR052: 7, AR202: 7, AR200: 6,AR206: 6, AR176: 6, AR269: 6, AR235: 6, AR272: 6, AR217: 6, AR055: 6,AR182: 6, AR264: 6, AR275: 6, AR061: 6, AR183: 5, AR168: 5, AR171: 5,AR309: 5, AR270: 5, AR228: 5, AR290: 5, AR268: 5, AR310: 5, AR181: 5,AR257: 5, AR060: 5, AR255: 5, AR165: 5, AR191: 5, AR164: 5, AR274: 5,AR247: 5, AR246: 4, AR166: 4, AR178: 4, AR311: 4, AR291: 4, AR312: 4,AR236: 4, AR173: 4, AR249: 4, AR233: 4, AR240: 4, AR288: 4, AR174: 4,AR267: 4, AR239: 4, AR204: 4, AR185: 4, AR287: 4, AR172: 4, AR192: 4,AR297: 4, AR213: 4, AR194: 4, AR177: 4, AR294: 4, AR261: 4, AR184: 4,AR190: 4, AR170: 3, AR284: 3, AR262: 3, AR210: 3, AR188: 3, AR089: 3,AR313: 3, AR196: 3, AR298: 3, AR266: 3, AR175: 3, AR033: 3, AR260: 3,AR285: 3, AR189: 3, AR316: 3, AR231: 3, AR251: 3, AR293: 3, AR296: 3,AR237: 3, AR286: 3, AR265: 3, AR243: 3, AR277: 3, AR300: 3, AR039: 3,AR289: 3, AR315: 3, AR179: 3, AR271: 3, AR234: 3, AR263: 3, AR199: 3,AR283: 3, AR203: 3, AR096: 3, AR299: 3, AR295: 3, AR229: 3, AR230: 3,AR292: 3, AR180: 3, AR104: 2, AR198: 2, AR308: 2, AR219: 2, AR053: 2,AR218: 2, AR211: 2, AR205: 2, AR238: 2, AR241: 2, AR258: 2, AR256: 2,AR226: 2, AR232: 2, AR280: 2, AR169: 1, AR227: 1, AR259: 1, AR201: 1,L0805: 3, H0556: 2, H0046: 2, S0022: 2, L0764: 2, L0662: 2, L0748: 2,H0013: 1, H0050: 1, H0039: 1, H0040: 1, H0087: 1, T0042: 1, L0643: 1,L0794: 1, L0803: 1, L0804: 1, L0807: 1, L0809: 1, L0666: 1, H0144: 1,L0749: 1, L0779: 1 and L0758: 1. 95 HJMAA03 824062 105 527-556 AR207:12, AR309: 11, AR192: 11, AR252: 10, AR053: 9, AR212: 9, AR242: 9,AR235: 9, AR213: 8, AR215: 8, AR198: 8, AR170: 8, AR169: 8, AR161: 8,AR162: 8, AR253: 8, AR223: 8, AR165: 8, AR166: 8, AR263: 7, AR163: 7,AR164: 7, AR274: 7, AR224: 7, AR245: 7, AR264: 7, AR214: 7, AR195: 7,AR217: 7, AR174: 7, AR197: 7, AR261: 7, AR311: 7, AR221: 7, AR282: 6,AR308: 6, AR222: 6, AR240: 6, AR312: 6, AR205: 6, AR171: 6, AR168: 6,AR193: 6, AR313: 6, AR246: 6, AR177: 6, AR173: 6, AR277: 6, AR216: 6,AR247: 6, AR180: 6, AR225: 6, AR283: 5, AR269: 5, AR300: 5, AR089: 5,AR201: 5, AR272: 5, AR297: 5, AR189: 5, AR204: 5, AR183: 5, AR299: 5,AR175: 5, AR288: 5, AR176: 5, AR295: 5, AR271: 5, AR250: 5, AR096: 5,AR275: 5, AR270: 4, AR316: 4, AR196: 4, AR191: 4, AR286: 4, AR178: 4,AR290: 4, AR185: 4, AR268: 4, AR296: 4, AR291: 4, AR257: 4, AR033: 4,AR199: 4, AR181: 4, AR039: 4, AR236: 4, AR229: 4, AR243: 4, AR285: 4,AR254: 4, AR289: 4, AR238: 3, AR172: 3, AR293: 3, AR262: 3, AR190: 3,AR287: 3, AR179: 3, AR200: 3, AR055: 3, AR104: 3, AR060: 3, AR188: 3,AR239: 3, AR182: 3, AR233: 3, AR258: 3, AR294: 3, AR061: 3, AR237: 3,AR231: 3, AR234: 3, AR226: 3, AR203: 3, AR255: 3, AR232: 3, AR230: 2,AR211: 2, AR227: 2, AR228: 2, AR267: 2, AR210: 2, AR266: 2, AR219: 2,AR260: 1, AR218: 1, AR256: 1, L0749: 8, L0803: 5, L0748: 5, L0777: 5,L0794: 4, L0766: 4, L0804: 4, H0135: 3, H0551: 3, L0754: 3, L0599: 3,H0542: 3, H0556: 2, H0545: 2, H0674: 2, L0764: 2, L0774: 2, L0776: 2,L0655: 2, H0521: 2, L0439: 2, L0752: 2, L0731: 2, L0596: 2, H0395: 1,H0713: 1, H0483: 1, H0663: 1, S0358: 1, H0580: 1, H0329: 1, S0045: 1,H0453: 1, H0427: 1, H0599: 1, H0706: 1, H0150: 1, H0123: 1, L0471: 1,L0163: 1, H0051: 1, H0275: 1, S0003: 1, S0214: 1, H0628: 1, H0090: 1,H0040: 1, H0087: 1, T0067: 1, H0412: 1, H0494: 1, H0509: 1, H0633: 1,H0647: 1, S0344: 1, L0769: 1, L0637: 1, L0761: 1, L0772: 1, L0800: 1,L0374: 1, L0771: 1, L0363: 1, L0768: 1, L0806: 1, L0659: 1, L0382: 1,L0809: 1, L0545: 1, L0789: 1, L0666: 1, H0519: 1, H0659: 1, S0152: 1,S0404: 1, L0751: 1, L0747: 1, L0750: 1, L0779: 1, S0436: 1, L0608: 1,S0276: 1, H0543: 1, H0506: 1 and H0352: 1. 96 HJMAV41 862029 106 207-290AR104: 44, AR277: 28, AR283: 16, AR219: 12, AR316: 12, AR299: 10, AR240:10, AR055: 9, AR089: 9, AR218: 9, AR185: 9, AR039: 9, AR300: 8, AR313:8, AR282: 8, AR096: 8, AR060: 7, L0742: 15, L0439: 7, S0007: 5, L0741:4, H0135: 3, L0516: 2, H0052: 2, L0438: 2, L0426: 1, H0402: 1, H0351: 1,S0222: 1, H0441: 1, H0333: 1, H0545: 1, S0388: 1, S0038: 1, L0351: 1,L0370: 1, L0770: 1, L0769: 1, L5566: 1, L0805: 1, L0659: 1, L0792: 1,L0793: 1, H0547: 1, L0750: 1, L0759: 1, L0366: 1, H0008: 1, H0721: 1 andH0352: 1. 97 HJMAY90 793678 107 2492-2596 AR283: 23, AR277: 22, AR089:21, AR313: 18, AR316: 18, AR282: 18, AR240: 17, AR300: 17, AR185: 16,AR096: 14, AR219: 14, AR299: 14, AR218: 14, AR104: 13, AR055: 13, AR039:12, AR060: 11, L0777: 9, L0757: 9, L0764: 8, L0809: 6, L0747: 6, H0674:4, L0783: 4, L0666: 4, L0748: 4, L0751: 4, L0731: 4, L0591: 4, L0770: 3,L0372: 3, L0662: 3, L0775: 3, L0518: 3, H0658: 3, L0604: 3, H0638: 2,S0360: 2, L0769: 2, L0761: 2, L0766: 2, L0804: 2, L0663: 2, H0520: 2,S3012: 2, S0027: 2, S0206: 2, L0439: 2, L0750: 2, L0779: 2, L0759: 2,L0600: 2, S6024: 1, H0295: 1, H0341: 1, S0001: 1, S0356: 1, S0376: 1,H0580: 1, H0735: 1, S0222: 1, H0455: 1, H0574: 1, H0632: 1, H0427: 1,H0599: 1, H0318: 1, H0052: 1, H0263: 1, H0231: 1, H0546: 1, H0545: 1,H0009: 1, H0620: 1, H0083: 1, H0687: 1, H0252: 1, H0615: 1, H0029: 1,H0032: 1, H0673: 1, H0135: 1, H0100: 1, L0564: 1, H0641: 1, H0646: 1,H0652: 1, S0426: 1, L0640: 1, L0638: 1, L0667: 1, L0772: 1, L0800: 1,L0768: 1, L0784: 1, L0805: 1, L0655: 1, L0659: 1, L0517: 1, L0526: 1,S0052: 1, L0438: 1, H0682: 1, S0330: 1, S0380: 1, H0521: 1, L0740: 1,L0786: 1, L0780: 1, L0752: 1, S0436: 1, L0605: 1, L0599: 1, S0026: 1 and: 1. 98 HJPBE39 801960 108 170-226 AR214: 33, AR171: 25, AR217: 24,AR223: 24, AR225: 23, AR168: 21, AR170: 21, AR172: 20, AR215: 19, AR216:18, AR169: 16, AR237: 13, AR224: 13, AR222: 10, AR233: 10, AR238: 10,AR239: 10, AR221: 9, AR061: 8, AR228: 7, AR231: 7, AR257: 7, AR165: 7,AR089: 6, AR218: 6, AR164: 6, AR163: 6, AR162: 6, AR285: 6, AR161: 6,AR166: 6, AR210: 6, AR286: 6, AR269: 6, AR294: 5, AR247: 5, AR055: 5,AR309: 5, AR297: 5, AR234: 5, AR316: 5, AR275: 5, AR229: 5, AR312: 5,AR287: 5, AR181: 5, AR190: 4, AR179: 4, AR270: 4, AR240: 4, AR282: 4,AR104: 4, AR175: 4, AR199: 4, AR300: 4, AR060: 4, AR258: 4, AR173: 4,AR293: 4, AR180: 4, AR291: 4, AR219: 4, AR189: 4, AR205: 4, AR299: 4,AR182: 4, AR193: 4, AR243: 4, AR255: 4, AR283: 4, AR200: 4, AR204: 4,AR311: 4, AR295: 4, AR203: 4, AR289: 4, AR290: 4, AR242: 4, AR262: 4,AR185: 4, AR176: 4, AR254: 3, AR250: 3, AR188: 3, AR227: 3, AR288: 3,AR296: 3, AR313: 3, AR264: 3, AR268: 3, AR174: 3, AR201: 3, AR053: 3,AR096: 3, AR177: 3, AR261: 3, AR178: 3, AR232: 3, AR236: 3, AR308: 3,AR260: 3, AR235: 3, AR277: 3, AR191: 3, AR197: 3, AR213: 3, AR226: 3,AR183: 3, AR253: 3, AR263: 3, AR267: 3, AR211: 3, AR246: 3, AR033: 3,AR212: 3, AR195: 2, AR196: 2, AR039: 2, AR256: 2, AR266: 2, AR271: 2,AR230: 2, AR192: 2, AR207: 2, AR272: 2, AR198: 1, L0375: 8, L0809: 7,L0794: 6, S0410: 5, L0803: 5, H0309: 4, S0003: 4, S0422: 4, L0592: 4,S0358: 3, H0747: 3, H0251: 3, H0494: 3, L0065: 3, S0438: 3, H0529: 3,S0378: 3, S0044: 3, S0406: 3, L0439: 3, L0751: 3, L0747: 3, L0731: 3,S0436: 3, L0608: 3, H0685: 2, S0114: 2, S0408: 2, T0008: 2, S0278: 2,H0497: 2, L0622: 2, H0046: 2, S0050: 2, H0083: 2, T0006: 2, H0166: 2,H0413: 2, H0625: 2, S0144: 2, S0344: 2, L0369: 2, L0763: 2, L0800: 2,L0764: 2, L0768: 2, L0499: 2, L0804: 2, L0775: 2, L0376: 2, L0518: 2,L4508: 2, L0666: 2, L0663: 2, L0438: 2, H0518: 2, L0750: 2, L0777: 2,L0753: 2, L0755: 2, L0758: 2, L0759: 2, H0445: 2, L0591: 2, L0599: 2,H0624: 1, H0170: 1, L0615: 1, S0134: 1, H0650: 1, S0116: 1, H0306: 1,H0402: 1, S0420: 1, S0356: 1, S0376: 1, S0444: 1, S0360: 1, H0580: 1,S0007: 1, S0046: 1, H0393: 1, L0717: 1, H0351: 1, H0453: 1, H0592: 1,H0586: 1, S0005: 1, H0559: 1, L0586: 1, H0013: 1, S0280: 1, H0618: 1,T0048: 1, H0318: 1, H0052: 1, H0085: 1, H0231: 1, H0544: 1, H0081: 1,S0388: 1, S0051: 1, H0071: 1, H0375: 1, H0266: 1, H0188: 1, S0214: 1,L0055: 1, H0674: 1, L0455: 1, H0124: 1, H0040: 1, T0042: 1, H0429: 1,S0352: 1, S0440: 1, S0142: 1, H0538: 1, S0002: 1, L0520: 1, L0371: 1,L0770: 1, L3904: 1, L0761: 1, L0667: 1, L0772: 1, L0646: 1, L0642: 1,L0374: 1, L0648: 1, L0662: 1, L0381: 1, L0650: 1, L0774: 1, L0805: 1,L0653: 1, L0776: 1, L0606: 1, L0657: 1, L0659: 1, L0517: 1, L0542: 1,L0384: 1, L0382: 1, L0543: 1, L5622: 1, L5623: 1, L0791: 1, L5286: 1,L0665: 1, L2257: 1, L2263: 1, L0710: 1, L2264: 1, T0068: 1, H0684: 1,H0435: 1, H0670: 1, H0648: 1, H0672: 1, H0539: 1, H0754: 1, H0710: 1,S0152: 1, H0555: 1, H0626: 1, S3012: 1, L0742: 1, L0748: 1, L0779: 1,S0434: 1, L0596: 1, L0361: 1, S0192: 1, H0542: 1, H0543: 1, H0422: 1,S0424: 1, L3563: 1, H0775: 1 and H0352: 1. 99 HJPCH08 840365 109 374-727AR277: 9, AR055: 9, AR218: 8, AR060: 6, AR219: 6, AR283: 5, AR300: 5,AR104: 5, AR240: 5, AR316: 5, AR185: 5, AR313: 5, AR299: 4, AR089: 3,AR096: 3, AR039: 3, AR282: 2, L0758: 9, L0777: 8, H0618: 6, L0794: 6,L0749: 6, L0774: 4, L0748: 4, L0750: 4, S0418: 3, S0358: 3, H0266: 3,L0770: 3, L0766: 3, L0759: 3, S0360: 2, H0150: 2, H0087: 2, L0369: 2,L0769: 2, L0771: 2, L0789: 2, L0663: 2, L0665: 2, H0422: 2, H0556: 1,H0295: 1, H0370: 1, H0331: 1, H0013: 1, L0021: 1, L0022: 1, H0253: 1,H0052: 1, H0204: 1, H0544: 1, H0012: 1, H0620: 1, H0024: 1, H0083: 1,H0510: 1, H0416: 1, H0252: 1, H0424: 1, H0617: 1, L0564: 1, H0494: 1,S0144: 1, L0372: 1, L0646: 1, L0800: 1, L0641: 1, L0764: 1, L0649: 1,L0803: 1, L0650: 1, L0775: 1, L0776: 1, L0655: 1, L0659: 1, L0809: 1,L0666: 1, L0664: 1, H0144: 1, H0521: 1, H0436: 1, S3012: 1, L0747: 1,L0786: 1, L0757: 1, L0608: 1 and L0595: 1. 100 HKGBF25 738797 110261-371 AR313: 16, AR039: 12, AR300: 10, AR299: 9, AR096: 9, AR218: 8,AR277: 8, AR089: 6, AR185: 5, AR316: 5, AR219: 5, AR104: 4, AR282: 3,AR240: 3, AR055: 3, AR060: 2, H0538: 1 101 HKIXC44 716213 111 572-682AR104: 28, AR055: 19, AR240: 15, AR219: 11, AR218: 11, AR185: 10, AR060:9, AR299: 7, AR089: 7, AR283: 7, AR282: 6, AR096: 5, AR316: 5, AR300: 5,AR313: 5, AR039: 4, AR277: 3, L0770: 7, L0742: 5, L0439: 4, L0776: 3,S0358: 2, H0619: 2, S0222: 2, L0769: 2, L0638: 2, L0796: 2, L0805: 2,H0593: 2, L0753: 2, L0485: 2, L0608: 2, H0329: 1, H0351: 1, H0441: 1,H0611: 1, H0370: 1, H0013: 1, H0196: 1, H0052: 1, H0251: 1, H0041: 1,H0024: 1, H0622: 1, S0366: 1, H0623: 1, L0648: 1, L0523: 1, L0806: 1,L0788: 1, L0666: 1, L0663: 1, H0648: 1, H0539: 1, S0152: 1, L0612: 1,L0777: 1, L0599: 1 and S0242: 1. 102 HKTAB41 695732 112 172-204 AR277:83, AR283: 74, AR219: 65, AR313: 56, AR316: 50, AR089: 49, AR218: 47,AR282: 46, AR104: 45, AR055: 42, AR185: 41, AR299: 40, AR096: 35, AR039:31, AR240: 31, AR060: 26, AR300: 25, L0794: 5, H0574: 1 and H0239: 1.103 HLDBG17 855953 113 184-309 AR313: 205, AR096: 153, AR240: 136,AR282: 133, AR219: 128, AR218: 116, AR299: 111, AR316: 101, AR277: 94,AR089: 89, AR039: 84, AR300: 83, AR283: 82, AR185: 77, AR060: 59, AR104:50, AR055: 37, L0581: 185, H0509: 97, H0510: 36, H0014: 25, H0355: 18,H0393: 14, L0748: 13, H0574: 12, H0331: 9, H0057: 5, H0144: 5, H0015: 3,L0605: 3, H0357: 2, H0427: 2, L0663: 2, L0749: 2, L0756: 2, H0662: 1,H0351: 1, H0349: 1, H0047: 1, H0038: 1, L0521: 1, L0518: 1, L0809: 1,L0787: 1, L0438: 1, L0439: 1, L0747: 1, L0759: 1 and S0412: 1. 104HLDQU79 740755 114  99-1142 AR253: 8, AR171: 7, AR245: 6, AR243: 5,AR183: 5, AR263: 5, AR264: 4, AR250: 4, AR269: 4, AR060: 4, AR180: 4,AR270: 4, AR309: 4, AR162: 4, AR268: 4, AR161: 4, AR165: 4, AR192: 4,AR176: 4, AR164: 4, AR055: 4, AR163: 4, AR213: 4, AR195: 4, AR271: 4,AR166: 3, AR275: 3, AR240: 3, AR282: 3, AR312: 3, AR246: 3, AR178: 3,AR181: 3, AR311: 3, AR168: 3, AR289: 3, AR182: 3, AR193: 3, AR217: 3,AR179: 3, AR212: 3, AR237: 3, AR238: 3, AR299: 3, AR199: 3, AR252: 3,AR229: 3, AR242: 2, AR185: 2, AR300: 2, AR277: 2, AR175: 2, AR293: 2,AR257: 2, AR308: 2, AR177: 2, AR198: 2, AR061: 2, AR214: 2, AR174: 2,AR104: 2, AR231: 2, AR316: 2, AR201: 2, AR233: 2, AR230: 2, AR224: 2,AR236: 2, AR239: 2, AR228: 2, AR188: 2, AR223: 2, AR189: 2, AR247: 2,AR294: 2, AR226: 2, AR266: 2, AR221: 2, AR285: 2, AR191: 2, AR089: 2,AR216: 2, AR200: 2, AR207: 2, AR272: 2, AR232: 2, AR190: 2, AR290: 2,AR283: 2, AR096: 2, AR222: 2, AR296: 2, AR039: 2, AR267: 2, AR205: 2,AR211: 1, AR196: 1, AR173: 1, AR033: 1, AR218: 1, AR295: 1, AR255: 1,AR262: 1, AR215: 1, AR227: 1, AR254: 1, AR234: 1, AR313: 1, AR203: 1,AR256: 1, AR169: 1, AR225: 1, AR210: 1, AR170: 1, L0748: 9, L0731: 7,L0771: 6, L0759: 6, H0013: 5, L0764: 4, L0747: 4, L0758: 4, H0265: 3,H0039: 3, H0038: 3, L0769: 3, L0766: 3, L0775: 3, H0144: 3, L0755: 3,S0444: 2, S0476: 2, H0318: 2, H0050: 2, L0471: 2, H0266: 2, L0374: 2,L0649: 2, L0805: 2, L0663: 2, L0664: 2, H0547: 2, S0126: 2, H0670: 2,L0740: 2, L0754: 2, L0750: 2, L0593: 2, H0667: 2, H0170: 1, H0171: 1,H0685: 1, H0662: 1, S0354: 1, S0360: 1, H0580: 1, H0728: 1, H0151: 1,H0747: 1, L3388: 1, H0357: 1, H0586: 1, H0331: 1, H0574: 1, H0635: 1,H0575: 1, H0263: 1, H0596: 1, H0545: 1, H0012: 1, H0620: 1, H0350: 1,H0355: 1, H0510: 1, H0428: 1, H0604: 1, H0031: 1, H0553: 1, S0366: 1,H0040: 1, H0063: 1, H0059: 1, H0560: 1, H0561: 1, S0440: 1, S0422: 1,H0529: 1, L0640: 1, L0637: 1, L0761: 1, L0772: 1, L0646: 1, L4556: 1,L0774: 1, L0375: 1, L0653: 1, L0382: 1, L5622: 1, L0793: 1, L4501: 1,H0723: 1, L0352: 1, S0152: 1, S0350: 1, H0521: 1, H0696: 1, S0044: 1,H0627: 1, S0027: 1, L0749: 1, L0752: 1, H0595: 1, S0436: 1, L0591: 1,L0595: 1, L0361: 1, S0011: 1, S0194: 1, S0276: 1 and H0423: 1. HLDQU79837599 253  75-1121 105 HLDRT09 830544 115 522-719 AR283: 10, AR277: 8,AR104: 8, AR282: 7, AR185: 7, AR039: 7, AR313: 6, AR089: 6, AR316: 6,AR060: 5, AR299: 5, AR300: 5, AR096: 5, AR055: 5, AR240: 4, AR219: 4,AR218: 3, L0493: 15, L0511: 11, L0500: 7, L0508: 6, L0514: 6, L0510: 6,L0504: 4, L0794: 4, L0499: 4, L0758: 4, L0507: 3, L0497: 3, L0439: 3,H0509: 2, L0505: 2, L0502: 2, L0503: 2, L0501: 2, L0509: 2, L0779: 2,H0265: 1, H0717: 1, H0656: 1, S0116: 1, H0483: 1, S0360: 1, H0431: 1,H0370: 1, L0015: 1, L0021: 1, H0744: 1, H0510: 1, H0181: 1, H0617: 1,H0708: 1, H0040: 1, H0633: 1, L0769: 1, L0639: 1, L3905: 1, L0667: 1,L0521: 1, L0662: 1, L0768: 1, L0649: 1, L0803: 1, L0804: 1, L0775: 1,L0515: 1, L0809: 1, L5622: 1, L0789: 1, L0791: 1, L0666: 1, H0144: 1,H0682: 1, H0659: 1, H0660: 1, H0672: 1, H0696: 1, L0748: 1, L0750: 1,S0192: 1 and L0697: 1. 106 HLHAP05 638476 116 45-89 L0005: 3, H0024: 2,H0209: 1 and H0445: 1. 107 HLHCS23 560663 117 ‘25-129 AR055: 5, AR060:4, AR185: 3, AR218: 3, AR240: 3, AR300: 3, AR282: 3, AR299: 2, AR039: 2,AR283: 2, AR089: 2, AR219: 2, AR316: 2, AR104: 2, AR096: 1, AR277: 1,H0024: 1 108 HLIBO72 883431 118 167-550 AR313: 63, AR241: 58, AR039: 49,AR192: 37, AR218: 35, AR183: 34, AR229: 32, AR096: 31, AR280: 31, AR299:31, AR258: 30, AR219: 28, AR226: 28, AR300: 27, AR177: 27, AR293: 27,AR198: 27, AR240: 26, AR312: 26, AR238: 26, AR185: 25, AR275: 24, AR089:24, AR175: 24, AR247: 23, AR249: 23, AR292: 23, AR259: 22, AR314: 21,AR316: 21, AR233: 20, AR243: 20, AR053: 20, AR179: 19, AR052: 18, AR231:18, AR315: 18, AR237: 18, AR294: 18, AR104: 17, AR256: 17, AR265: 17,AR248: 17, AR281: 17, AR234: 17, AR213: 16, AR309: 15, AR271: 15, AR277:15, AR251: 15, AR282: 14, AR033: 14, AR295: 13, AR204: 13, AR186: 13,AR244: 13, AR263: 13, AR227: 13, AR253: 12, AR310: 12, AR194: 11, AR267:11, AR273: 11, AR274: 11, AR060: 11, AR269: 10, AR270: 10, AR268: 9,AR232: 8, AR184: 7, AR246: 7, AR206: 7, AR205: 7, AR182: 7, AR266: 6,AR290: 6, AR055: 5, AR202: 5, AR296: 4, AR291: 4, AR283: 4, AR289: 3,AR061: 3, AR285: 3, AR284: 3, AR298: 3, AR286: 3, L0764: 2, L0662: 2,L0748: 2, L0731: 2, L0758: 2, S0212: 1, S0442: 1, S0376: 1, S0444: 1,S0360: 1, T0039: 1, H0545: 1, H0355: 1, S0214: 1, H0553: 1, L0055: 1,H0090: 1, H0551: 1, H0412: 1, H0413: 1, H0494: 1, S0438: 1, H0509: 1,H0652: 1, S0142: 1, L0772: 1, L0767: 1, L0794: 1, L0803: 1, L0659: 1,L0383: 1, L0545: 1, L0664: 1, H0682: 1, H0670: 1, S0380: 1, H0521: 1,H0522: 1, H0436: 1, S3014: 1, S0027: 1, L0754: 1, L0752: 1, S0434: 1,L0593: 1, H0653: 1, H0665: 1 and S0196: 1. 109 HLICE88 840321 119708-716 AR185: 21, AR240: 19, AR104: 13, AR039: 13, AR060: 13, AR089:13, AR300: 12, AR282: 11, AR096: 11, AR055: 10, AR316: 10, AR219: 10,AR218: 9, AR299: 7, AR283: 7, AR313: 7, AR277: 4, H0014: 72, L3388: 60,H0509: 49, L0581: 44, H0355: 43, H0574: 32, H0393: 30, H0632: 21, H0510:18, S0438: 18, H0098: 15, H0144: 14, H0331: 13, H0015: 8, L0748: 8,H0722: 7, L3387: 7, H0741: 5, H0013: 5, H0147: 4, T0078: 4, L0615: 3,H0357: 3, S0440: 3, H0730: 2, H0349: 2, H0350: 2, H0057: 2, H0644: 2,H0647: 2, L0605: 2, L0599: 2, H0170: 1, L0448: 1, H0149: 1, L0393: 1,S0444: 1, L3645: 1, H0749: 1, L2255: 1, H0351: 1, H0642: 1, H0427: 1,H0003: 1, H0575: 1, H0199: 1, H0040: 1, H0745: 1, L0787: 1, L0747: 1 andS0436: 1. 110 HLICO10 658740 120 441-659 AR096: 23, AR313: 20, AR299:19, AR219: 19, AR089: 17, AR240: 17, AR218: 16, AR316: 15, AR060: 13,AR282: 12, AR039: 11, AR185: 11, AR104: 10, AR283: 9, AR277: 9, AR300:7, AR055: 7, L0766: 9, L0758: 8, L0747: 7, L0749: 7, L0771: 6, L0776: 6,L0439: 6, L0748: 5, L0596: 5, L0770: 4, L0740: 4, H0622: 3, L0483: 3,L0662: 3, L0666: 3, S0418: 2, S0376: 2, S0360: 2, S0408: 2, H0747: 2,H0251: 2, L0646: 2, L0764: 2, L0768: 2, L0774: 2, L0806: 2, L0517: 2,L0663: 2, L0664: 2, L0744: 2, L0750: 2, L0756: 2, L0752: 2, L0731: 2,L0757: 2, L0759: 2, H0265: 1, L3643: 1, L0002: 1, L0785: 1, S0001: 1,H0661: 1, H0662: 1, S0420: 1, S0354: 1, S0222: 1, H0333: 1, H0635: 1,H0156: 1, H0002: 1, H0042: 1, H0575: 1, L0105: 1, H0374: 1, H0052: 1,H0085: 1, L0471: 1, T0010: 1, H0355: 1, H0060: 1, T0006: 1, H0111: 1,H0561: 1, S0440: 1, S0142: 1, L0763: 1, L0769: 1, L4747: 1, L0796: 1,L5565: 1, L0761: 1, L0372: 1, L0377: 1, L0381: 1, L0375: 1, L0655: 1,L0657: 1, L0793: 1, L0532: 1, L0665: 1, L0438: 1, H0519: 1, H0690: 1,S0330: 1, S0380: 1, S0152: 1, S0406: 1, H0555: 1, L0754: 1, L0745: 1,L0755: 1, H0444: 1, S0434: 1, S0436: 1, L0599: 1, L0362: 1, L0601: 1,H0543: 1 and L0600: 1. 111 HLJBS28 658742 121 359-412 AR313: 15, AR316:9, AR096: 9, AR218: 7, AR299: 7, AR039: 7, AR300: 7, AR089: 5, AR219: 5,AR282: 5, AR055: 5, AR104: 4, AR185: 4, AR277: 4, AR060: 3, AR283: 2,L0766: 8, L0803: 3, H0659: 3, L0758: 3, L0598: 2, L0649: 2, L0805: 2,L0655: 2, L0731: 2, L0759: 2, S0342: 1, H0657: 1, L3388: 1, L0021: 1,H0375: 1, H0615: 1, H0428: 1, L0638: 1, L0637: 1, L0651: 1, L0659: 1,L0791: 1, H0648: 1, S0328: 1, H0752: 1, L0744: 1, L0747: 1, L0756: 1,L0752: 1, H0423: 1 and H0422: 1. 112 HLMJB64 658699 122  12-161 H0521:11, L0751: 9, L0777: 9, H0255: 8, L0747: 8, S0360: 7, L0766: 7, H0542:7, L0754: 6, L0749: 6, L0757: 6, H0265: 5, H0052: 5, L0659: 5, L0665: 5,S0126: 5, H0539: 5, L0748: 5, L0439: 5, L0740: 5, L0758: 5, L0759: 5,H0624: 4, H0717: 4, H0046: 4, H0024: 4, H0551: 4, L0776: 4, L0438: 4,L0602: 4, L0743: 4, L0779: 4, H0575: 3, H0253: 3, H0545: 3, H0266: 3,H0284: 3, H0039: 3, H0068: 3, H0509: 3, L0770: 3, L0769: 3, L0662: 3,L0774: 3, L0809: 3, L0666: 3, L0663: 3, H0435: 3, H0672: 3, H0522: 3,S0406: 3, S0028: 3, L0752: 3, L0731: 3, H0543: 3, H0171: 2, H0556: 2,H0716: 2, S0212: 2, H0638: 2, S0376: 2, H0586: 2, H0333: 2, L0021: 2,H0599: 2, H0036: 2, H0618: 2, H0581: 2, H0050: 2, L0163: 2, H0644: 2,H0040: 2, H0087: 2, S0038: 2, H0494: 2, S0144: 2, S0002: 2, L0369: 2,L0763: 2, L0637: 2, L0800: 2, L0773: 2, L0803: 2, L0375: 2, L0806: 2,L0655: 2, L0657: 2, H0144: 2, L0565: 2, H0689: 2, H0660: 2, H0436: 2,L0750: 2, S0436: 2, L0596: 2, L0589: 2, L0485: 2, L0604: 2, S0192: 2,S0242: 2, L0718: 2, S0040: 1, H0713: 1, S0134: 1, S0430: 1, H0341: 1,H0483: 1, H0671: 1, S0418: 1, S0420: 1, L0005: 1, S0442: 1, S0354: 1,S0358: 1, H0637: 1, S0045: 1, S0046: 1, S0140: 1, S0132: 1, S0476: 1,H0645: 1, H0351: 1, H0549: 1, H0550: 1, S0222: 1, H0441: 1, H0370: 1,L0468: 1, H0592: 1, H0587: 1, H0497: 1, H0559: 1, L0622: 1, T0114: 1,H0013: 1, H0069: 1, H0635: 1, H0427: 1, H0097: 1, H0042: 1, T0082: 1,H0318: 1, H0546: 1, H0123: 1, L0471: 1, H0620: 1, H0014: 1, H0051: 1,H0201: 1, S0051: 1, H0510: 1, H0286: 1, H0428: 1, T0006: 1, H0424: 1,H0628: 1, H0606: 1, H0673: 1, H0124: 1, H0038: 1, H0634: 1, H0063: 1,H0379: 1, H0272: 1, H0488: 1, H0412: 1, H0413: 1, S0382: 1, S0438: 1,S0142: 1, S0344: 1, S0210: 1, S0426: 1, L0506: 1, L0639: 1, L0761: 1,L0772: 1, L0646: 1, L0643: 1, L0644: 1, L0771: 1, L0648: 1, L0521: 1,L0794: 1, L0649: 1, L0775: 1, L0651: 1, L0378: 1, L0805: 1, L0807: 1,L0518: 1, L0783: 1, L0791: 1, L0664: 1, S0052: 1, S0216: 1, H0702: 1,H0701: 1, S0374: 1, H0520: 1, H0682: 1, H0683: 1, H0658: 1, H0670: 1,H0666: 1, S0328: 1, S0380: 1, S0404: 1, H0555: 1, H0576: 1, H0627: 1,L0612: 1, S3012: 1, S0037: 1, L0780: 1, S0031: 1, H0444: 1, H0445: 1,S0434: 1, L0588: 1, L0593: 1, S0011: 1, S0026: 1, H0667: 1, S0194: 1,S0196: 1, H0423: 1, H0422: 1, S0042: 1 and H0506: 1. 113 HLWAV47 897769123 200-298 AR277: 35, AR283: 29, AR282: 27, AR316: 23, AR313: 20,AR219: 19, AR089: 18, AR104: 17, AR240: 17, AR299: 16, AR055: 16, AR218:16, AR300: 16, AR185: 15, AR096: 15, AR039: 11, AR060: 10, L0754: 7,L0803: 4, H0553: 3, H0478: 2, L0745: 2, L0753: 2, H0170: 1, H0057: 1,L0163: 1, S6028: 1, L0598: 1, L0666: 1, L0663: 1 and H0144: 1. 114HLYDF73 566869 124 363-434 AR277: 12, AR283: 9, AR282: 6, AR316: 6,AR300: 5, AR055: 5, AR089: 5, AR104: 4, AR299: 4, AR185: 4, AR096: 4,AR218: 4, AR313: 4, AR240: 4, AR039: 3, AR219: 3, AR060: 2, H0445: 1 115HLYGE16 651339 125 406-627 AR055: 2, AR185: 2, AR316: 1, AR060: 1,AR283: 1, H0255: 5, H0144: 3, H0429: 2, L0662: 2, L0794: 2, L0803: 2,L0809: 2, L0758: 2, L0599: 2, H0542: 2, S0040: 1, H0650: 1, S0442: 1,H0642: 1, L0157: 1, H0571: 1, H0673: 1, H0494: 1, L0771: 1, L0766: 1,L0776: 1, L0629: 1, L0657: 1, L0659: 1, L0792: 1, L0565: 1, H0345: 1,L0748: 1, L0754: 1, L0747: 1, L0749: 1, H0445: 1 and S0242: 1. 116HLYGY91 658703 126 211-339 AR313: 6, AR316: 5, AR218: 3, AR300: 3,AR299: 3, AR055: 3, AR185: 2, AR039: 2, AR096: 2, AR277: 2, AR219: 1,AR089: 1, H0692: 10, L0777: 10, L0805: 5, L0803: 3, L2497: 2, H0328: 2,L0662: 2, L0794: 2, L0809: 2, L3832: 2, L0748: 2, L0752: 2, L0599: 2,H0170: 1, H0402: 1, S0444: 1, S0360: 1, H0747: 1, L2486: 1, L3503: 1,H0427: 1, H0644: 1, H0038: 1, L0800: 1, L0648: 1, L0804: 1, H0670: 1,H0478: 1, L0731: 1, L0758: 1, H0445: 1, S0434: 1, L0591: 1 and L0362: 1.117 HMCFH60 654853 127 211-357 AR104: 113, AR219: 90, AR218: 87, AR089:82, AR283: 79, AR277: 79, AR313: 78, AR055: 75, AR240: 71, AR316: 70,AR185: 63, AR282: 60, AR299: 59, AR096: 54, AR039: 50, AR060: 48, AR300:38, L0659: 10, T0040: 9, L0665: 9, L0759: 9, L0519: 8, L0776: 7, S0436:7, L0744: 6, L0747: 6, L0749: 6, L0758: 6, S0418: 5, H0052: 5, H0457: 5,H0150: 5, L0769: 5, L0766: 5, L0748: 5, H0265: 4, S0420: 4, S0356: 4,S0360: 4, S0046: 4, S0010: 4, H0545: 4, H0687: 4, H0494: 4, S0440: 4,L0662: 4, L0768: 4, L0774: 4, L0775: 4, L0751: 4, L0754: 4, L0779: 4,H0484: 3, H0734: 3, H0549: 3, H0599: 3, H0421: 3, H0620: 3, S0051: 3,L0764: 3, L0666: 3, H0435: 3, H0648: 3, H0539: 3, L0596: 3, H0543: 3,H0624: 2, H0171: 2, H0556: 2, H0295: 2, H0657: 2, H0656: 2, S0354: 2,S0358: 2, S0376: 2, S0408: 2, S0007: 2, S0132: 2, S0476: 2, S0222: 2,H0486: 2, T0039: 2, H0635: 2, H0156: 2, H0618: 2, T0048: 2, H0581: 2,H0544: 2, H0373: 2, H0428: 2, T0006: 2, H0604: 2, H0031: 2, H0551: 2,T0067: 2, H0264: 2, H0647: 2, S0344: 2, L0638: 2, L0372: 2, L0641: 2,L0806: 2, L0653: 2, L0527: 2, L0809: 2, L0565: 2, L0438: 2, H0519: 2,H0689: 2, H0658: 2, H0672: 2, S0330: 2, S0406: 2, H0436: 2, S0027: 2,L0750: 2, S0434: 2, L0605: 2, S0194: 2, H0506: 2, H0685: 1, H0713: 1,H0717: 1, H0740: 1, H0294: 1, S0212: 1, S0110: 1, S0282: 1, H0483: 1,S0442: 1, H0637: 1, H0733: 1, S0468: 1, H0747: 1, L3388: 1, H0351: 1,H0550: 1, H0587: 1, H0642: 1, H0559: 1, L0622: 1, L3653: 1, H0013: 1,H0250: 1, H0069: 1, S0280: 1, H0706: 1, S0346: 1, H0705: 1, H0318: 1,S0049: 1, H0748: 1, L0040: 1, H0597: 1, L0738: 1, H0009: 1, H0563: 1,H0123: 1, H0050: 1, L0471: 1, H0012: 1, H0024: 1, H0014: 1, S0388: 1,H0239: 1, H0594: 1, S6028: 1, H0271: 1, H0292: 1, H0213: 1, H0628: 1,H0673: 1, H0068: 1, S0036: 1, H0135: 1, H0090: 1, H0038: 1, H0634: 1,H0087: 1, H0488: 1, H0268: 1, H0412: 1, H0413: 1, S0038: 1, T0042: 1,H0560: 1, H0641: 1, S0210: 1, S0422: 1, S0002: 1, H0529: 1, L0770: 1,L0637: 1, L3905: 1, L5566: 1, L0761: 1, L0772: 1, L0646: 1, L0374: 1,L0771: 1, L4500: 1, L0651: 1, L0784: 1, L0807: 1, L0657: 1, L0658: 1,L0656: 1, L0782: 1, L0783: 1, L0530: 1, L0647: 1, L0788: 1, L0663: 1,L0664: 1, S0216: 1, H0693: 1, L3826: 1, H0520: 1, H0547: 1, S0126: 1,H0682: 1, H0659: 1, S0328: 1, S0380: 1, H0710: 1, H0521: 1, H0522: 1,H0627: 1, S0028: 1, L0741: 1, L0742: 1, L0439: 1, L0740: 1, L0756: 1,L0786: 1, L0780: 1, L0755: 1, L0581: 1, L0595: 1, L0601: 1, H0667: 1,S0192: 1, H0542: 1, L0718: 1 and S0424: 1. 118 HMDAB29 584789 128 97-177 AR313: 127, AR039: 86, AR299: 64, AR089: 56, AR185: 51, AR096:50, AR277: 50, AR300: 42, AR316: 37, AR240: 33, AR218: 27, AR219: 25,AR104: 22, AR060: 22, AR282: 20, AR055: 16, AR283: 9, H0346: 1, H0598: 1and S0330: 1. 119 HMDAD44 566854 129 135-161 AR277: 44, AR283: 35,AR219: 28, AR316: 26, AR089: 24, AR218: 23, AR313: 22, AR282: 22, AR055:22, AR104: 21, AR299: 20, AR185: 19, AR240: 19, AR096: 17, AR039: 16,AR060: 14, AR300: 14, L0749: 3, H0346: 1, H0370: 1, H0427: 1 andL0439: 1. 120 HMEDI90 840077 130 622-675 AR104: 7, AR316: 6, AR055: 5,AR060: 5, AR300: 4, AR185: 4, AR218: 4, AR282: 3, AR283: 3, AR240: 3,AR089: 3, AR219: 2, AR299: 2, AR039: 1, AR313: 1, AR096: 1, AR277: 1,L0439: 8, S6028: 2, H0266: 2, L0438: 2, L0745: 2, L0717: 1, S0222: 1,H0052: 1, H0194: 1, H0009: 1, T0010: 1, S0036: 1, L0776: 1, L0789: 1,S0028: 1, L0756: 1 and L0779: 1. 121 HMIAK10 562774 131 195-290 AR055:7, AR218: 7, AR060: 6, AR219: 6, AR185: 4, AR283: 4, AR240: 4, AR300: 4,AR104: 3, AR089: 3, AR299: 3, AR039: 3, AR316: 2, AR277: 2, AR096: 2,AR313: 2, AR282: 2, S6028: 1 122 HMIBF07 603528 132 229-249 AR055: 5,AR060: 4, AR240: 4, AR300: 3, AR299: 3, AR104: 3, AR283: 3, AR219: 2,AR218: 2, AR185: 2, AR039: 2, AR089: 2, AR277: 2, AR096: 2, AR316: 2,AR282: 1, AR313: 1, S6028: 1 123 HMICI80 827318 133 1149-1247 AR104: 21,AR316: 11, AR055: 6, AR060: 6, AR282: 5, AR218: 5, AR299: 4, AR185: 4,AR300: 4, AR240: 3, AR089: 3, AR039: 3, AR283: 3, AR096: 2, AR313: 2,AR277: 2, AR219: 1, L0439: 17, H0569: 3, L0438: 3, L0415: 2, H0156: 2,S0049: 2, H0052: 2, S0388: 2, L0805: 2, L0809: 2, L0748: 2, L0777: 2,L0592: 2, S0045: 1, S0222: 1, S0346: 1, H0563: 1, S0051: 1, S6028: 1,S0036: 1, L0789: 1, L0756: 1 and L0755: 1. 124 HMJAK70 610099 134273-305 AR251: 4, AR052: 3, AR263: 3, AR269: 3, AR265: 2, AR282: 2,AR253: 2, AR309: 2, AR238: 2, AR271: 2, AR186: 2, AR247: 2, AR270: 2,AR266: 1, AR277: 1, AR312: 1, AR053: 1, AR295: 1, AR241: 1, AR237: 1,AR310: 1, AR213: 1, AR182: 1, AR175: 1, AR313: 1, AR268: 1, AR226: 1,AR096: 1, H0391: 1 125 HMTAB77 847411 135 769-915 AR297: 10, AR287: 9,AR288: 9, AR225: 9, AR291: 7, AR171: 5, AR221: 5, AR296: 5, AR285: 5,AR255: 5, AR193: 4, AR178: 4, AR294: 4, AR168: 4, AR169: 4, AR217: 4,AR295: 4, AR170: 4, AR235: 4, AR224: 4, AR223: 4, AR216: 4, AR180: 4,AR261: 4, AR245: 4, AR293: 3, AR222: 3, AR308: 3, AR262: 3, AR243: 3,AR289: 3, AR257: 3, AR195: 3, AR270: 3, AR253: 3, AR162: 3, AR163: 3,AR205: 3, AR286: 3, AR161: 3, AR173: 3, AR290: 3, AR184: 3, AR254: 3,AR165: 3, AR192: 3, AR236: 3, AR172: 3, AR164: 3, AR179: 2, AR269: 2,AR181: 2, AR183: 2, AR166: 2, AR267: 2, AR260: 2, AR190: 2, AR312: 2,AR201: 2, AR175: 2, AR258: 2, AR039: 2, AR212: 2, AR247: 2, AR096: 2,AR174: 2, AR282: 2, AR292: 2, AR191: 2, AR268: 2, AR189: 2, AR266: 2,AR313: 2, AR316: 1, AR089: 1, AR213: 1, AR264: 1, AR277: 1, AR219: 1,AR060: 1, AR299: 1, AR263: 1, AR188: 1, AR182: 1, AR200: 1, AR300: 1,AR196: 1, AR226: 1, AR240: 1, AR210: 1, AR177: 1, AR234: 1, H0436: 65,L0747: 25, H0521: 12, L0754: 11, L0471: 7, L0439: 7, S0358: 6, S0360: 5,L0809: 5, H0520: 5, L0731: 5, L0757: 5, L0599: 5, H0580: 4, H0581: 4,S0003: 4, H0551: 4, S0440: 4, L0803: 4, L0775: 4, L0517: 4, H0547: 4,H0519: 4, H0539: 4, L0750: 4, S0436: 4, H0624: 3, H0717: 3, L3001: 3,L2491: 3, H0575: 3, S0474: 3, H0373: 3, H0428: 3, H0090: 3, H0616: 3,H0529: 3, L2654: 3, H0144: 3, H0518: 3, L0744: 3, L0752: 3, L0758: 3,S0192: 3, H0171: 2, H0716: 2, S0001: 2, H0669: 2, S0418: 2, S0420: 2,L0562: 2, S0356: 2, S0442: 2, S0354: 2, S0444: 2, H0393: 2, S0222: 2,H0592: 2, H0586: 2, H0333: 2, L3816: 2, T0040: 2, H0156: 2, S0049: 2,H0052: 2, H0046: 2, H0457: 2, H0687: 2, L0455: 2, H0040: 2, H0412: 2,H0560: 2, S0208: 2, S0422: 2, L0520: 2, L0770: 2, L0769: 2, L3905: 2,L0764: 2, L0648: 2, L0662: 2, L0794: 2, L0805: 2, L0518: 2, L0783: 2,L0789: 2, L2264: 2, L2675: 2, L3829: 2, H0658: 2, S0152: 2, S0406: 2,H0555: 2, L0748: 2, L0740: 2, L0759: 2, H0445: 2, S0434: 2, L0362: 2,S0026: 2, S0194: 2, H0542: 2, H0543: 2, S0424: 2, H0352: 2, H0149: 1,S0040: 1, H0583: 1, L0453: 1, L3814: 1, L2910: 1, H0341: 1, S0212: 1,H0671: 1, H0663: 1, L2289: 1, L3659: 1, H0638: 1, L0005: 1, H0735: 1,S0045: 1, H0749: 1, H0619: 1, H0411: 1, H0175: 1, H0369: 1, H0431: 1,H0392: 1, H0455: 1, H0612: 1, H0587: 1, H0331: 1, L0622: 1, H0486: 1,H0635: 1, H0599: 1, H0098: 1, S0010: 1, H0318: 1, H0310: 1, H0263: 1,T0110: 1, H0545: 1, N0006: 1, H0123: 1, H0050: 1, H0011: 1, H0620: 1,L0163: 1, T0010: 1, H0083: 1, H0375: 1, S6028: 1, H0028: 1, S0250: 1,S0214: 1, H0328: 1, H0039: 1, H0031: 1, H0553: 1, H0124: 1, H0598: 1,S0036: 1, H0038: 1, H0063: 1, T0067: 1, H0264: 1, H0413: 1, H0623: 1,S0038: 1, H0100: 1, L0564: 1, T0042: 1, H0494: 1, H0625: 1, H0561: 1,S0150: 1, L0598: 1, L0763: 1, L0761: 1, L0667: 1, L0641: 1, L0650: 1,L0375: 1, L0523: 1, L0654: 1, L0776: 1, L0807: 1, L0647: 1, L0792: 1,L0793: 1, L0666: 1, L0664: 1, L0665: 1, L2657: 1, L2260: 1, H0699: 1,L2439: 1, S0374: 1, L0438: 1, L3827: 1, L3210: 1, H0689: 1, H0435: 1,H0659: 1, H0670: 1, H0660: 1, L0602: 1, L3832: 1, H0627: 1, S0037: 1,S0027: 1, L3327: 1, L0743: 1, L0749: 1, L0779: 1, L2138: 1, H0595: 1,L0605: 1, L0485: 1, L0604: 1, L0593: 1, L0594: 1, S0196: 1, S0412: 1,L3566: 1 and L3378: 1. 126 HMUAE26 747403 136 710-802 AR277: 29, AR283:26, AR282: 19, AR316: 17, AR240: 16, AR219: 15, AR313: 14, AR300: 14,AR089: 14, AR096: 13, AR218: 13, AR104: 13, AR299: 13, AR185: 11, AR055:11, AR039: 10, AR060: 9, S0406: 5, H0305: 3, S0422: 3, L0743: 3, H0617:2, L0770: 2, L0794: 2, L0384: 2, L0666: 2, L0777: 2, L0591: 2, L0595: 2,H0556: 1, H0717: 1, S0418: 1, S0358: 1, S0410: 1, H0734: 1, S0045: 1,H0497: 1, H0493: 1, H0618: 1, H0318: 1, H0581: 1, H0012: 1, H0620: 1,H0014: 1, T0010: 1, H0292: 1, S0250: 1, H0615: 1, H0428: 1, H0087: 1,H0551: 1, L0351: 1, H0560: 1, H0132: 1, H0529: 1, L5565: 1, L3905: 1,L0761: 1, L0644: 1, L0375: 1, L0524: 1, L0653: 1, L0655: 1, L0656: 1,L0809: 1, L0791: 1, H0520: 1, H0547: 1, H0690: 1, H0682: 1, H0670: 1,H0672: 1, S0404: 1, H0555: 1, L0749: 1, L0779: 1, L0780: 1, L0731: 1,H0445: 1, H0653: 1, S0192: 1 and H0542: 1. 127 HMUAN45 833072 137239-922 AR236: 442, AR228: 429, AR211: 336, AR230: 331, AR287: 325,AR191: 311, AR239: 297, AR174: 289, AR233: 252, AR232: 252, AR190: 238,AR288: 237, AR176: 228, AR203: 222, AR262: 218, AR260: 210, AR199: 209,AR181: 193, AR173: 191, AR163: 186, AR178: 181, AR200: 175, AR162: 165,AR189: 164, AR297: 164, AR166: 154, AR161: 154, AR164: 149, AR188: 148,AR227: 147, AR234: 145, AR261: 144, AR311: 142, AR257: 141, AR210: 140,AR179: 139, AR165: 137, AR272: 136, AR295: 134, AR226: 134, AR255: 130,AR231: 129, AR180: 129, AR285: 127, AR196: 127, AR308: 126, AR275: 123,AR286: 123, AR177: 118, AR238: 117, AR258: 116, AR235: 114, AR237: 104,AR294: 100, AR175: 99, AR264: 98, AR182: 96, AR212: 96, AR293: 93,AR185: 92, AR291: 90, AR267: 79, AR229: 78, AR061: 75, AR240: 74, AR060:74, AR256: 73, AR269: 65, AR104: 64, AR247: 63, AR274: 60, AR201: 60,AR300: 59, AR033: 56, AR263: 53, AR289: 51, AR183: 49, AR193: 48, AR290:43, AR195: 41, AR316: 40, AR270: 40, AR296: 37, AR282: 36, AR312: 34,AR197: 33, AR218: 33, AR277: 29, AR299: 29, AR055: 28, AR089: 28, AR250:27, AR268: 27, AR207: 26, AR309: 25, AR053: 25, AR252: 24, AR266: 21,AR213: 20, AR242: 19, AR224: 19, AR219: 19, AR313: 18, AR223: 18, AR169:18, AR222: 17, AR171: 17, AR168: 16, AR172: 16, AR205: 15, AR217: 14,AR096: 14, AR245: 14, AR214: 14, AR204: 12, AR225: 12, AR170: 11, AR246:11, AR254: 11, AR198: 11, AR283: 10, AR192: 10, AR216: 10, AR271: 9,AR253: 9, AR215: 8, AR221: 7, AR039: 5, AR243: 4, AR184: 1, AR310: 1,H0271: 5, H0083: 3, L0794: 3, H0656: 2, H0457: 2, H0179: 2, L0791: 2,H0521: 2, L0744: 2, H0707: 2, H0265: 1, H0556: 1, H0657: 1, H0449: 1,H0580: 1, S0046: 1, H0411: 1, H0437: 1, H0333: 1, H0486: 1, H0250: 1,S6028: 1, H0615: 1, H0628: 1, L0055: 1, H0040: 1, H0634: 1, S0144: 1,H0529: 1, L0769: 1, L0768: 1, L0766: 1, L0803: 1, L0653: 1, L0793: 1,L0666: 1, S0052: 1, H0689: 1, H0522: 1, H0436: 1, L0743: 1, L0749: 1,L0779: 1, H0445: 1 and H0542: 1. 128 HMVBC31 825598 138 1437-1559 AR055:5, AR316: 4, AR218: 3, AR282: 3, AR104: 2, AR283: 2, AR185: 2, AR096: 2,AR313: 2, AR240: 2, AR060: 2, AR300: 2, AR299: 1, AR277: 1, AR089: 1,AR039: 1, L0748: 10, H0556: 5, S0442: 5, L0438: 4, L0439: 4, L0754: 4,H0050: 3, H0040: 3, L0769: 3, L0806: 3, L0757: 3, L0759: 3, L0601: 3,T0002: 2, S0418: 2, S0358: 2, S0360: 2, H0580: 2, S0476: 2, H0549: 2,H0644: 2, H0529: 2, L0773: 2, L0768: 2, L0766: 2, L0805: 2, L0776: 2,L0663: 2, L0740: 2, L0747: 2, L0749: 2, S0436: 2, H0717: 1, S0212: 1,H0484: 1, H0661: 1, S0376: 1, H0729: 1, H0733: 1, S0007: 1, H0643: 1,L0622: 1, L3653: 1, H0013: 1, H0042: 1, H0052: 1, L0157: 1, L0471: 1,H0373: 1, H0083: 1, H0266: 1, T0006: 1, H0090: 1, H0268: 1, H0494: 1,H0509: 1, H0633: 1, H0646: 1, S0422: 1, S0002: 1, L0761: 1, L0772: 1,L0643: 1, L0644: 1, L0794: 1, L0803: 1, L0555: 1, L0659: 1, L0783: 1,L0809: 1, L5622: 1, H0690: 1, H0658: 1, S0328: 1, S0330: 1, S0152: 1,H0521: 1, H0696: 1, S0044: 1, S0027: 1, L0780: 1, L0752: 1, L0753: 1,L0755: 1, S0434: 1, L0485: 1, H0667: 1, S0276: 1 and S0456: 1. 129HMWBL03 822861 139  137-1327 AR313: 27, AR299: 16, AR219: 16, AR218: 14,AR316: 12, AR300: 6, AR039: 5, AR089: 5, AR055: 5, AR060: 4, AR240: 4,AR096: 4, AR282: 4, AR283: 3, AR277: 3, AR185: 3, AR104: 2, S0422: 18,L0766: 7, H0341: 5, S0356: 5, H0543: 5, H0591: 4, H0656: 3, S0354: 3,H0013: 3, T0042: 3, H0659: 3, L0748: 3, L0750: 3, L0777: 3, S0418: 2,S0442: 2, S0444: 2, S0410: 2, L0471: 2, H0040: 2, H0063: 2, H0494: 2,L0646: 2, L0626: 2, L0806: 2, L0655: 2, L0663: 2, S0374: 2, H0547: 2,S0206: 2, L0756: 2, S0436: 2, L0588: 2, H0624: 1, H0171: 1, S0342: 1,H0650: 1, S0360: 1, T0008: 1, H0733: 1, S0046: 1, H0257: 1, H0263: 1,L0738: 1, H0046: 1, L0157: 1, H0039: 1, H0068: 1, H0135: 1, H0090: 1,T0041: 1, H0560: 1, S0440: 1, H0529: 1, L0640: 1, L0771: 1, L0768: 1,L0634: 1, L0529: 1, L5623: 1, L0666: 1, L0665: 1, H0520: 1, H0519: 1,S0328: 1, S0152: 1, S0406: 1, L0751: 1, L0747: 1, L0759: 1, L0591: 1,L0608: 1, H0542: 1, H0423: 1 and H0721: 1. 130 HMWCG28 847413 140 78-200 L0439: 19, L0740: 16, L0748: 15, L0766: 12, H0052: 7, L0761: 7,L0741: 7, L0747: 7, H0135: 6, L0769: 6, L0438: 6, S0036: 4, L0770: 4,L0806: 4, L0752: 4, L0731: 4, H0327: 3, H0012: 3, T0010: 3, L0794: 3,L0803: 3, L0783: 3, L0809: 3, L0744: 3, L0758: 3, L0601: 3, H0341: 2,H0550: 2, H0333: 2, L0622: 2, H0599: 2, H0618: 2, H0318: 2, H0051: 2,S0388: 2, S0051: 2, H0100: 2, L0772: 2, L0774: 2, L0664: 2, S0380: 2,L0751: 2, L0745: 2, L0779: 2, L0777: 2, L0753: 2, L0485: 2, H0265: 1,H0381: 1, H0483: 1, S0418: 1, S0354: 1, S0444: 1, S0360: 1, S0046: 1,S0278: 1, H0261: 1, H0455: 1, H0438: 1, H0574: 1, H0559: 1, L0623: 1,H0706: 1, T0048: 1, H0581: 1, H0251: 1, H0597: 1, H0544: 1, H0046: 1,H0457: 1, H0009: 1, H0081: 1, H0620: 1, H0200: 1, H0095: 1, H0275: 1,H0083: 1, H0354: 1, H0266: 1, H0328: 1, H0428: 1, H0070: 1, T0023: 1,H0673: 1, H0124: 1, H0038: 1, H0087: 1, L0351: 1, L0564: 1, H0560: 1,H0130: 1, S0344: 1, L0369: 1, L0763: 1, L0637: 1, L5575: 1, L5565: 1,L3905: 1, L0667: 1, L0641: 1, L0645: 1, L0764: 1, L0775: 1, L0376: 1,L0776: 1, L0606: 1, L0659: 1, L0789: 1, L0666: 1, L0663: 1, L0665: 1,H0693: 1, H0547: 1, H0660: 1, H0539: 1, S0044: 1, H0436: 1, L0742: 1,L0749: 1, L0755: 1, L0759: 1, S0031: 1, S0260: 1, H0445: 1, H0707: 1,S0434: 1, L0581: 1, L0593: 1, S0194: 1, H0543: 1, H0423: 1 and H0506: 1.131 HNECW49 639117 141 316-489 AR055: 8, AR060: 7, AR240: 6, AR185: 5,AR300: 5, AR218: 5, AR104: 5, AR283: 5, AR089: 4, AR299: 4, AR282: 4,AR316: 3, AR039: 3, AR313: 3, AR096: 3, AR277: 2, AR219: 2, H0179: 2 andH0402: 1. 132 HNFCY57 877653 142 317-2206 H0271: 3, H0575: 2, H0416: 2,H0518: 2, L0748: 2, S6022: 1, L0021: 1, H0024: 1, H0179: 1, S0002: 1,L0794: 1, S0053: 1 and S0216: 1. 133 HNFGR08 825417 143 314-445 AR055:5, AR060: 4, AR185: 3, AR240: 3, AR300: 2, AR104: 2, AR282: 2, AR089: 2,AR283: 2, AR219: 2, AR218: 2, AR316: 1, AR039: 1, AR096: 1, H0271: 1 134HNGAK51 603910 144 248-346 AR313: 60, AR039: 47, AR299: 29, AR277: 29,AR089: 26, AR185: 24, AR096: 23, AR240: 20, AR300: 19, AR316: 17, AR218:14, AR060: 14, AR219: 14, AR104: 14, AR055: 11, AR282: 10, AR283: 6,S0052: 1 135 HNGAM58 688114 145  68-412 AR313: 88, AR039: 72, AR299: 41,AR185: 40, AR300: 34, AR089: 34, AR277: 32, AR096: 31, AR218: 23, AR316:23, AR240: 23, AR104: 21, AR219: 20, AR060: 16, AR282: 14, AR055: 9,AR283: 6, S0052: 1 136 HNGDX18 1145071 146 237-965 AR228: 8, AR176: 7,AR161: 6, AR162: 6, AR163: 6, AR251: 5, AR223: 5, AR181: 5, AR171: 5,AR225: 4, AR060: 4, AR267: 4, AR055: 4, AR216: 4, AR261: 4, AR235: 4,AR236: 4, AR268: 4, AR230: 4, AR269: 4, AR288: 4, AR191: 4, AR052: 4,AR182: 4, AR221: 4, AR239: 4, AR254: 3, AR242: 3, AR255: 3, AR312: 3,AR233: 3, AR287: 3, AR272: 3, AR262: 3, AR165: 3, AR271: 3, AR244: 3,AR178: 3, AR229: 3, AR164: 3, AR173: 3, AR257: 3, AR290: 3, AR274: 3,AR266: 3, AR061: 3, AR297: 3, AR166: 3, AR282: 3, AR198: 3, AR053: 3,AR231: 3, AR199: 3, AR291: 3, AR177: 3, AR201: 3, AR214: 3, AR264: 3,AR247: 3, AR196: 3, AR224: 3, AR190: 3, AR174: 3, AR270: 3, AR296: 2,AR286: 2, AR300: 2, AR309: 2, AR203: 2, AR089: 2, AR200: 2, AR294: 2,AR289: 2, AR249: 2, AR311: 2, AR240: 2, AR168: 2, AR293: 2, AR238: 2,AR188: 2, AR217: 2, AR175: 2, AR285: 2, AR179: 2, AR234: 2, AR310: 2,AR185: 2, AR033: 2, AR298: 2, AR260: 2, AR226: 2, AR316: 2, AR227: 2,AR222: 2, AR313: 2, AR265: 2, AR197: 2, AR277: 2, AR237: 2, AR189: 2,AR295: 2, AR299: 2, AR193: 2, AR283: 2, AR172: 2, AR183: 2, AR275: 2,AR232: 2, AR211: 2, AR253: 2, AR210: 2, AR104: 2, AR096: 2, AR213: 1,AR258: 1, AR292: 1, AR308: 1, AR273: 1, AR194: 1, AR180: 1, AR184: 1,AR284: 1, AR252: 1, AR205: 1, H0457: 4, S0052: 4, H0271: 3, L0766: 3,H0543: 3, H0255: 2, H0402: 2, H0253: 2, L0805: 2, L0754: 2, H0422: 2,H0583: 1, H0650: 1, H0656: 1, H0484: 1, H0483: 1, H0254: 1, L3659: 1,S0442: 1, S0360: 1, H0580: 1, S0140: 1, H0747: 1, H0393: 1, H0486: 1,H0250: 1, H0618: 1, H0050: 1, H0630: 1, H0719: 1, H0182: 1, H0063: 1,H0087: 1, H0264: 1, H0488: 1, H0487: 1, L0351: 1, T0042: 1, S0448: 1,S0002: 1, L0761: 1, L0378: 1, L0655: 1, L4501: 1, H0539: 1, S0188: 1,S0146: 1, H0707: 1, L0599: 1, H0136: 1, H0423: 1 and H0677: 1. 137HNGEQ75 535723 147 30-98 H0052: 2, H0406: 1, S0052: 1 and L0439: 1. 138HNGFR54 695748 148  73-231 S0052: 2 139 HNGGA68 638116 149 184-282AR055: 6, AR060: 6, AR218: 6, AR300: 4, AR185: 4, AR240: 4, AR299: 3,AR104: 3, AR219: 3, AR089: 3, AR282: 3, AR283: 3, AR316: 3, AR096: 2,AR039: 2, AR313: 2, AR277: 2, H0419: 1, H0305: 1 and S0052: 1. 140HNGHZ69 899289 150 25-54 H0445: 2 and S0052: 1. 141 HNGKT41 836061 151415-552 AR316: 11, AR055: 6, AR060: 6, AR277: 5, AR300: 5, AR282: 5,AR104: 4, AR240: 4, AR185: 4, AR218: 3, AR283: 3, AR313: 3, AR039: 3,AR089: 3, AR219: 3, AR096: 2, AR299: 2, S0428: 1 142 HNGMW45 838613 152452-583 AR316: 3, S0428: 1 143 HNGNO53 836063 153 467-571 AR055: 7,AR060: 6, AR240: 5, AR300: 5, AR218: 5, AR185: 4, AR283: 4, AR299: 4,AR277: 4, AR089: 4, AR104: 3, AR316: 3, AR096: 3, AR219: 2, AR313: 2,AR039: 2, AR282: 1, S0428: 2 and L0439: 1. 144 HNGPJ25 834942 154544-621 AR060: 7, AR055: 7, AR218: 6, AR240: 6, AR282: 5, AR185: 5,AR277: 5, AR300: 5, AR299: 4, AR283: 3, AR089: 3, AR104: 3, AR316: 3,AR096: 3, AR039: 2, AR313: 2, AR219: 2, H0251: 8, H0624: 4, L0752: 4,H0286: 1, L0598: 1, S0428: 1 and H0144: 1. 145 HNHFE71 834487 155598-663 AR055: 9, AR060: 8, AR218: 6, AR300: 5, AR185: 5, AR240: 5,AR277: 5, AR299: 5, AR282: 5, AR104: 5, AR283: 4, AR089: 4, AR039: 4,AR316: 4, AR096: 3, AR313: 3, AR219: 2, S0053: 1 146 HNHGK22 597451 156239-433 AR060: 7, AR055: 6, AR240: 5, AR218: 4, AR185: 4, AR299: 4,AR300: 4, AR089: 4, AR104: 4, AR282: 4, AR283: 3, AR039: 3, AR316: 3,AR313: 3, AR096: 3, AR219: 3, S0053: 2 147 HNHKS19 778392 157 192-317L0789: 2, H0616: 1, S0216: 1 and L0758: 1. 148 HNHKV56 800877 158294-494 S0216: 1 and L0746: 1. 149 HOACG07 792928 159  778-1149 AR202:138, AR194: 120, AR315: 99, AR281: 99, AR198: 98, AR244: 88, AR246: 86,AR243: 85, AR205: 85, AR192: 82, AR241: 80, AR280: 79, AR204: 73, AR265:70, AR283: 66, AR206: 63, AR310: 59, AR263: 57, AR271: 57, AR314: 56,AR273: 54, AR053: 50, AR052: 49, AR282: 49, AR033: 48, AR277: 47, AR275:46, AR213: 45, AR274: 44, AR312: 43, AR316: 43, AR309: 42, AR104: 40,AR240: 40, AR300: 40, AR289: 39, AR096: 39, AR266: 38, AR251: 37, AR247:36, AR089: 36, AR299: 36, AR284: 35, AR313: 35, AR186: 34, AR039: 33,AR055: 33, AR175: 32, AR219: 31, AR295: 31, AR291: 29, AR177: 28, AR218:28, AR185: 27, AR268: 26, AR285: 26, AR270: 25, AR286: 25, AR253: 24,AR183: 24, AR060: 24, AR232: 23, AR061: 23, AR292: 23, AR298: 23, AR258:22, AR256: 20, AR248: 20, AR296: 19, AR182: 19, AR238: 18, AR269: 18,AR290: 18, AR294: 18, AR267: 17, AR231: 17, AR226: 17, AR259: 17, AR229:16, AR227: 16, AR234: 16, AR293: 15, AR233: 15, AR237: 14, AR249: 13,AR184: 13, AR179: 11, L0748: 4, L0749: 4, H0265: 3, S0442: 2, H0587: 2,H0427: 2, S0142: 2, L0769: 2, L0761: 2, L0800: 2, L0794: 2, L0657: 2,L0659: 2, L0663: 2, L0665: 2, H0689: 2, L0731: 2, H0677: 2, H0713: 1,H0716: 1, H0657: 1, H0661: 1, H0638: 1, S0360: 1, H0722: 1, H0122: 1,H0545: 1, H0009: 1, H0123: 1, S0388: 1, H0252: 1, T0023: 1, T0006: 1,H0135: 1, H0163: 1, H0412: 1, L0351: 1, S0440: 1, H0529: 1, L0372: 1,L0646: 1, L0645: 1, L0764: 1, L0662: 1, L0767: 1, L0766: 1, L0649: 1,L0803: 1, L0776: 1, L0655: 1, L0382: 1, L0809: 1, L0789: 1, H0672: 1,H0627: 1, L0751: 1, L0750: 1, L0753: 1, L0757: 1, L0758: 1 and L0759: 1.150 HODBB70 520196 160 173-256 AR055: 7, AR218: 6, AR060: 5, AR104: 5,AR240: 4, AR300: 4, AR299: 4, AR096: 4, AR219: 4, AR283: 4, AR039: 3,AR185: 3, AR089: 3, AR316: 3, AR282: 3, AR277: 2, H0328: 1, L0789: 1,L0742: 1 and L0439: 1. 151 HOEBK60 789396 161 1714-1845 AR219: 21,AR218: 19, AR316: 12, AR313: 10, AR039: 9, AR096: 8, AR089: 8, AR299: 7,AR240: 7, AR055: 7, AR300: 7, AR060: 7, AR282: 6, AR185: 5, AR283: 5,AR104: 4, AR277: 4, L0439: 10, L0731: 7, L0605: 6, L0766: 5, L0803: 5,L0471: 4, L0655: 4, L0659: 4, L0756: 4, S0408: 3, S0440: 3, H0648: 3,L0777: 3, H0170: 2, S0420: 2, L0021: 2, H0014: 2, T0010: 2, L0143: 2,H0090: 2, H0591: 2, H0641: 2, L0638: 2, L0662: 2, L0794: 2, L0776: 2,L0657: 2, L0809: 2, L0666: 2, L0663: 2, H0547: 2, S0126: 2, H0518: 2,L0751: 2, L0755: 2, L0758: 2, L0588: 2, H0543: 2, H0624: 1, H0740: 1,S0430: 1, H0657: 1, H0656: 1, S0212: 1, S0110: 1, H0661: 1, H0663: 1,S0442: 1, S0358: 1, S0376: 1, S0360: 1, S0476: 1, L0717: 1, L0586: 1,T0114: 1, H0427: 1, L0105: 1, H0318: 1, S0474: 1, H0581: 1, H0052: 1,H0309: 1, L0157: 1, H0024: 1, H0071: 1, H0275: 1, H0354: 1, S6028: 1,H0266: 1, S0003: 1, H0328: 1, H0615: 1, H0428: 1, H0031: 1, H0169: 1,H0163: 1, H0038: 1, H0040: 1, H0551: 1, H0272: 1, T0041: 1, S0014: 1,S0438: 1, H0646: 1, S0142: 1, S0210: 1, S0426: 1, H0529: 1, L0372: 1,L0645: 1, L0764: 1, L0651: 1, L0656: 1, L5623: 1, L0789: 1, L0665: 1,H0520: 1, H0689: 1, H0682: 1, H0435: 1, H0659: 1, S0380: 1, H0696: 1,L0740: 1, L0754: 1, L0746: 1, L0750: 1, L0779: 1, L0752: 1, S0260: 1,S0434: 1, S0436: 1, L0485: 1 and H0423: 1. 152 HOFNB74 762821 162138-257 AR277: 18, AR283: 18, AR282: 14, AR313: 12, AR316: 11, AR055: 9,AR089: 9, AR240: 8, AR104: 8, AR218: 8, AR299: 8, AR096: 8, AR219: 8,AR300: 7, AR185: 7, AR039: 6, AR060: 5, H0415: 1 153 HOSDO75 862049 163 88-174 AR060: 6, AR055: 6, AR218: 6, AR240: 5, AR277: 5, AR300: 4,AR185: 4, AR299: 4, AR283: 4, AR089: 4, AR282: 3, AR104: 3, AR316: 3,AR096: 3, AR313: 2, AR039: 2, AR219: 2, L0766: 2, L0362: 2, S0358: 1,H0580: 1, S0046: 1, H0266: 1, S0003: 1, H0553: 1, S0344: 1, L0761: 1,L0794: 1, S0152: 1, L0777: 1 and L0755: 1. 154 HOSEI81 562778 164203-454 AR055: 5, AR060: 5, AR104: 4, AR282: 4, AR300: 4, AR299: 3,AR185: 3, AR089: 3, AR240: 3, AR039: 3, AR283: 2, AR218: 2, AR096: 2,AR316: 2, AR219: 2, AR313: 2, AR277: 2, L0777: 2, S0214: 1 and H0539: 1.155 HOUDE92 580866 165  70-336 H0052: 17, L0745: 11, L0748: 10, H0547:7, L0439: 7, L0755: 6, L0771: 5, L0774: 5, L0662: 4, L0746: 4, L0777: 4,S0474: 3, L0163: 3, H0059: 3, H0100: 3, L0775: 3, L0741: 3, H0261: 2,H0333: 2, H0194: 2, H0545: 2, H0012: 2, H0617: 2, H0135: 2, L0770: 2,L0665: 2, L0438: 2, H0520: 2, L0747: 2, L0752: 2, L0753: 2, S0040: 1,L0717: 1, H0437: 1, H0550: 1, S6016: 1, H0497: 1, H0574: 1, H0599: 1,H0575: 1, H0618: 1, H0253: 1, H0041: 1, H0620: 1, H0373: 1, H0188: 1,H0124: 1, H0068: 1, H0040: 1, H0561: 1, S0448: 1, S0210: 1, L0763: 1,L0644: 1, L0767: 1, L0768: 1, L0375: 1, L0651: 1, L0659: 1, L0540: 1,L5622: 1, H0144: 1, H0593: 1, S0126: 1, H0539: 1, S0152: 1, H0694: 1,S0390: 1, S0028: 1, L0749: 1, L0786: 1, L0780: 1, L0731: 1, L0757: 1,L0758: 1, S0436: 1, L0592: 1 and S0276: 1. 156 HOVBD85 827362 166252-332 AR218: 13, AR219: 12, AR096: 5, AR313: 2, AR316: 2, AR055: 1,AR060: 1, AR282: 1, AR240: 1, H0252: 1, H0428: 1 and L0439: 1. 157HPCAB41 758003 167 184-261 AR104: 4, AR055: 4, AR277: 3, AR218: 3,AR282: 2, AR039: 2, AR299: 2, AR185: 2, AR283: 2, AR089: 2, AR060: 2,AR316: 2, AR219: 2, AR313: 1, AR300: 1, AR096: 1, L0754: 4, L0471: 1,L0662: 1, L0766: 1, H0521: 1, S0146: 1, L0758: 1 and H0422: 1. 158HPEAD23 773409 168 188-469 AR277: 68, AR283: 65, AR219: 61, AR316: 49,AR218: 41, AR089: 41, AR104: 39, AR299: 38, AR055: 36, AR185: 36, AR039:34, AR282: 33, AR240: 31, AR096: 31, AR313: 31, AR060: 30, AR300: 25,H0585: 18, L0779: 3, L0775: 2, S0374: 2, H0341: 1, S0358: 1, S0360: 1,S0408: 1, H0559: 1, T0039: 1, H0156: 1, H0253: 1, S0182: 1, H0318: 1,H0545: 1, H0083: 1, H0165: 1, L0768: 1, L0774: 1, L0750: 1, L0752: 1 andS0031: 1. 159 HPFCI36 855966 169  94-153 AR218: 18, AR219: 16, AR313:14, AR089: 9, AR055: 7, AR282: 6, AR060: 6, AR316: 6, AR185: 6, AR299:5, AR240: 5, AR039: 5, AR300: 4, AR104: 4, AR283: 4, AR096: 4, AR277: 2,L0591: 4, L0754: 3, H0450: 2, H0486: 2, H0046: 2, S0003: 2, H0494: 2,S0422: 2, L0659: 2, S0126: 2, H0659: 2, L0750: 2, L0601: 2, H0170: 1,H0556: 1, H0657: 1, S0420: 1, S0354: 1, H0734: 1, H0749: 1, H0455: 1,H0403: 1, H0600: 1, H0013: 1, H0156: 1, H0599: 1, H0744: 1, H0082: 1,S0214: 1, H0622: 1, H0031: 1, H0673: 1, H0169: 1, H0090: 1, H0038: 1,H0022: 1, H0560: 1, L0643: 1, L0771: 1, L0773: 1, L0655: 1, L0807: 1,L3872: 1, L0792: 1, L0665: 1, L3811: 1, S0378: 1, H0518: 1, S0152: 1,H0521: 1, L0748: 1, L0749: 1, L0757: 1, L0759: 1, S0434: 1, L0596: 1,L0605: 1 and H0653: 1. 160 HPFDI37 862056 170 38-91 AR055: 5, AR218: 5,AR060: 4, AR299: 3, AR300: 3, AR283: 3, AR104: 3, AR282: 3, AR240: 3,AR039: 2, AR219: 2, AR277: 2, AR185: 2, AR316: 2, AR089: 2, AR313: 2,AR096: 1, L0771: 13, L0752: 12, L0748: 9, L0731: 7, S0360: 6, L0769: 6,S0358: 5, H0318: 5, L0770: 5, L0747: 5, L0758: 5, L0599: 5, H0140: 4,H0545: 4, H0673: 4, L0774: 4, L0655: 4, L0659: 4, L0664: 4, L0665: 4,H0659: 4, H0648: 4, L0740: 4, L0754: 4, L0588: 4, H0662: 3, H0169: 3,H0413: 3, L0638: 3, L0775: 3, L0783: 3, L0666: 3, L0663: 3, H0660: 3,H0521: 3, L0749: 3, L0750: 3, L0757: 3, H0543: 3, H0170: 2, S0110: 2,H0574: 2, H0581: 2, H0535: 2, L0065: 2, H0647: 2, S0344: 2, L0763: 2,L0764: 2, L0662: 2, L0767: 2, L0803: 2, L0806: 2, L0776: 2, S0374: 2,S0328: 2, S0380: 2, H0576: 2, S0028: 2, L0591: 2, H0352: 2, H0265: 1,T0002: 1, H0686: 1, H0685: 1, H0295: 1, H0657: 1, L0760: 1, S0212: 1,H0484: 1, H0177: 1, H0638: 1, L0617: 1, L0005: 1, S0442: 1, S0376: 1,H0637: 1, H0411: 1, H0370: 1, H0587: 1, H0632: 1, T0109: 1, H0156: 1,H0085: 1, H0327: 1, H0530: 1, H0046: 1, H0041: 1, S0388: 1, H0630: 1,H0271: 1, H0644: 1, H0628: 1, H0181: 1, H0617: 1, H0674: 1, H0068: 1,H0040: 1, H0488: 1, L0564: 1, T0041: 1, H0494: 1, H0633: 1, S0144: 1,S0210: 1, S0422: 1, L0369: 1, L0762: 1, L0372: 1, L0646: 1, L0765: 1,L0363: 1, L0768: 1, L0651: 1, L0653: 1, L0629: 1, L0657: 1, L0526: 1,L0532: 1, S0053: 1, S0216: 1, H0144: 1, H0519: 1, S0126: 1, H0689: 1,H0690: 1, H0684: 1, S0027: 1, L0742: 1, L0756: 1, L0780: 1, L0755: 1,H0444: 1, H0445: 1, L0596: 1, L0605: 1, L0592: 1, L0593: 1, L0362: 1,L0603: 1 and H0136: 1. 161 HPIAA80 829972 171 314-427 AR218: 13, AR219:11, AR282: 9, AR089: 8, AR055: 8, AR240: 7, AR104: 6, AR060: 6, AR283:6, AR277: 6, AR039: 6, AR316: 5, AR299: 5, AR096: 4, AR185: 4, AR300: 4,AR313: 3, L0750: 3, H0672: 2, L0744: 2, H0587: 1, L0021: 1, S0010: 1,H0024: 1, H0266: 1, S0364: 1, H0068: 1, H0038: 1, T0004: 1, H0625: 1,S0150: 1, L0769: 1, L0667: 1, L0649: 1, L0784: 1, L0526: 1, L0790: 1,L0792: 1, L0793: 1, L0663: 1, H0696: 1, L0747: 1, L0608: 1 and S0276: 1.162 HPJCW58 612866 172 177-263 AR055: 8, AR060: 6, AR282: 6, AR218: 5,AR104: 4, AR300: 4, AR240: 4, AR283: 4, AR219: 4, AR299: 3, AR089: 3,AR185: 3, AR316: 3, AR096: 3, AR039: 2, AR277: 2, AR313: 1, S0152: 1 163HPMFH77 702014 173 251-358 AR089: 24, AR282: 22, AR060: 6, AR277: 5,AR055: 5, AR104: 4, AR240: 4, AR316: 4, AR299: 4, AR300: 4, AR313: 4,AR283: 4, AR039: 3, AR218: 2, AR096: 2, AR185: 2, L0750: 4, L0809: 3,L0747: 3, L0803: 2, L0776: 2, L0740: 2, L0754: 2, S0045: 1, S0010: 1,H0581: 1, T0010: 1, H0687: 1, H0031: 1, S0440: 1, L0770: 1, L0764: 1,L0375: 1, L0748: 1 and L0731: 1. 164 HPQCB83 740761 174  85-189 AR055:2, AR060: 2, AR282: 2, AR277: 1, AR185: 1, AR283: 1, AR240: 1, S0136: 15165 HPRBH85 695752 175 684-1088 AR284: 14, AR295: 10, AR271: 8, AR293:7, AR246: 7, AR243: 7, AR291: 7, AR244: 6, AR286: 6, AR290: 6, AR241: 6,AR285: 6, AR206: 6, AR310: 5, AR249: 5, AR273: 5, AR198: 5, AR280: 5,AR312: 5, AR186: 5, AR270: 5, AR294: 5, AR204: 5, AR269: 5, AR251: 5,AR202: 5, AR292: 5, AR275: 4, AR033: 4, AR253: 4, AR053: 4, AR182: 4,AR314: 4, AR259: 4, AR315: 4, AR298: 4, AR265: 4, AR309: 4, AR282: 4,AR274: 4, AR183: 4, AR061: 4, AR205: 4, AR296: 4, AR289: 4, AR052: 4,AR313: 4, AR175: 3, AR213: 3, AR238: 3, AR268: 3, AR248: 3, AR055: 3,AR177: 3, AR247: 3, AR231: 3, AR104: 3, AR256: 3, AR226: 2, AR185: 2,AR283: 2, AR277: 2, AR267: 2, AR227: 2, AR300: 2, AR096: 2, AR089: 2,AR258: 2, AR219: 2, AR263: 2, AR299: 2, AR237: 2, AR240: 2, AR060: 2,AR316: 2, AR218: 2, AR281: 2, AR039: 2, AR233: 1, AR232: 1, AR184: 1,AR234: 1, AR266: 1, AR192: 1, L0439: 5, L0740: 4, L0777: 4, L0755: 4,L0794: 2, L0803: 2, L0438: 2, L0602: 2, L0752: 2, L0599: 2, H0713: 1,H0583: 1, S0360: 1, L3653: 1, L0471: 1, H0510: 1, H0032: 1, H0488: 1,H0413: 1, L0662: 1, L0804: 1, L0775: 1, L0805: 1, L0655: 1, L0809: 1,L0519: 1, S0148: 1, H0547: 1, L0747: 1, L0686: 1 and H0665: 1. 166HPRCD35 853551 176 265-372 AR104: 14, AR089: 11, AR055: 11, AR185: 10,AR219: 10, AR299: 10, AR218: 10, AR313: 10, AR282: 10, AR240: 9, AR316:9, AR283: 9, AR096: 8, AR060: 7, AR039: 6, AR300: 5, AR277: 5, L0748: 5,L0754: 5, L0803: 4, L0805: 4, L0777: 4, L0662: 3, L0766: 3, H0556: 2,H0013: 2, H0551: 2, H0264: 2, L0800: 2, L0806: 2, L0664: 2, L0439: 2,L0756: 2, L0758: 2, S0192: 2, H0657: 1, S0442: 1, S0358: 1, S0045: 1,S0046: 1, H0747: 1, H0550: 1, H0392: 1, S0280: 1, H0575: 1, H0545: 1,H0046: 1, H0050: 1, H0644: 1, H0617: 1, L0055: 1, H0032: 1, H0212: 1,H0038: 1, H0560: 1, S0438: 1, S0210: 1, L0769: 1, L0796: 1, L5575: 1,L0768: 1, L0794: 1, L0649: 1, L0776: 1, L0659: 1, L0542: 1, L0526: 1,L0663: 1, H0144: 1, L0565: 1, L3811: 1, H0683: 1, H0659: 1, S0152: 1,H0521: 1, H0522: 1, H0540: 1, S0118: 1, S0032: 1, L0731: 1, L0759: 1 andH0668: 1. 167 HPTRM02 812879 177  885-1127 H0617: 7, H0087: 6, H0657: 5,S0410: 3, L0754: 3, S0356: 2, L0717: 2, H0150: 2, H0687: 2, H0424: 2,H0551: 2, L0769: 2, L0774: 2, L0743: 2, L0758: 2, L0592: 2, H0556: 1,T0002: 1, H0686: 1, H0685: 1, T0049: 1, H0663: 1, S0442: 1, S0444: 1,S0360: 1, S0476: 1, H0550: 1, H0486: 1, H0250: 1, L0021: 1, T0048: 1,S0474: 1, S0049: 1, H0052: 1, H0309: 1, H0597: 1, H0544: 1, H0014: 1,H0107: 1, S6028: 1, H0622: 1, H0644: 1, H0102: 1, S0038: 1, L0351: 1,S0450: 1, S0344: 1, S0002: 1, L0764: 1, L0766: 1, L0805: 1, L0776: 1,L0655: 1, L0661: 1, L0657: 1, L0809: 1, L0666: 1, L0665: 1, L2652: 1,L2260: 1, L2261: 1, H0689: 1, H0435: 1, H0521: 1, H0696: 1, H0555: 1,L0744: 1, L0439: 1, L0749: 1, L0777: 1, L0755: 1, L0759: 1, S0436: 1,L0597: 1, L0599: 1, L0366: 1 and S0196: 1. 168 HRADA42 827302 178122-256 AR283: 35, AR219: 34, AR277: 32, AR316: 28, AR218: 25, AR282:24, AR313: 23, AR104: 22, AR089: 22, AR096: 20, AR185: 19, AR299: 19,AR055: 17, AR300: 16, AR240: 16, AR039: 15, AR060: 13, L0771: 7, S0358:4, L0768: 4, L0779: 4, L0766: 3, L0775: 3, L0748: 3, L0754: 3, L0763: 2,L0769: 2, L0764: 2, L0649: 2, L0774: 2, L0809: 2, L0747: 2, H0657: 1,S0116: 1, H0671: 1, S0418: 1, L0005: 1, S0360: 1, S0408: 1, H0733: 1,S0045: 1, H0393: 1, H0370: 1, H0333: 1, H0150: 1, T0003: 1, H0266: 1,S0003: 1, L0055: 1, H0038: 1, H0040: 1, H0100: 1, S0440: 1, H0646: 1,S0344: 1, S0210: 1, S0422: 1, H0529: 1, L0770: 1, L0646: 1, L0767: 1,L0381: 1, L0378: 1, L0776: 1, L0655: 1, L0659: 1, L2264: 1, S0126: 1,H0659: 1, H0670: 1, H0648: 1, H0710: 1, H0555: 1, S0028: 1, L0740: 1,L0750: 1, L0777: 1, L0752: 1, L0755: 1, L0731: 1, L0758: 1, L0759: 1,S0434: 1, S0436: 1, L0596: 1, L0588: 1, L0605: 1, L0590: 1, L0608: 1 andH0543: 1. 169 HRADF49 866481 179 169-930 AR244: 12, AR296: 6, AR205: 6,AR183: 6, AR292: 6, AR104: 5, AR249: 5, AR291: 5, AR285: 5, AR298: 5,AR206: 5, AR289: 4, AR240: 4, AR293: 4, AR275: 4, AR270: 4, AR295: 4,AR294: 4, AR284: 3, AR213: 3, AR186: 3, AR060: 3, AR286: 3, AR234: 3,AR229: 3, AR282: 3, AR267: 3, AR184: 3, AR096: 3, AR283: 3, AR033: 3,AR251: 3, AR300: 2, AR313: 2, AR316: 2, AR185: 2, AR039: 2, AR299: 2,AR218: 2, AR256: 2, AR089: 2, AR219: 2, AR061: 2, AR243: 2, AR055: 2,AR269: 2, AR277: 2, AR233: 2, AR238: 2, AR182: 2, AR268: 2, AR175: 2,AR259: 2, AR266: 2, AR232: 2, AR258: 2, AR227: 2, AR315: 2, AR263: 1,AR226: 1, AR309: 1, AR314: 1, AR053: 1, AR290: 1, AR052: 1, AR231: 1,H0618: 9, L0751: 7, L0754: 6, L0758: 6, H0253: 5, L0748: 5, L0439: 5,H0580: 3, L3816: 3, H0052: 3, L0770: 3, L0663: 3, H0556: 2, H0733: 2,H0351: 2, H0706: 2, H0567: 2, H0625: 2, S0142: 2, L0639: 2, L3905: 2,L0659: 2, L0543: 2, L5623: 2, L0749: 2, S0436: 2, H0423: 2, L3643: 1,H0381: 1, S0212: 1, H0254: 1, H0663: 1, H0638: 1, S0418: 1, H0741: 1,H0735: 1, S0045: 1, S0046: 1, S0476: 1, S6022: 1, H0549: 1, H0550: 1,S0222: 1, H0370: 1, H0497: 1, H0574: 1, L0622: 1, L0623: 1, L3655: 1,H0101: 1, H0427: 1, S0280: 1, H0122: 1, H0194: 1, H0596: 1, H0570: 1,H0081: 1, H0620: 1, H0014: 1, H0083: 1, H0355: 1, H0510: 1, H0424: 1,H0030: 1, H0553: 1, H0628: 1, S0364: 1, S0366: 1, H0038: 1, H0551: 1,H0100: 1, L0351: 1, H0494: 1, S0438: 1, H0633: 1, S0144: 1, S0422: 1,L0371: 1, L0769: 1, L3904: 1, L0772: 1, L0648: 1, L0497: 1, L0375: 1,L0511: 1, L0666: 1, L0709: 1, L0710: 1, H0144: 1, L3811: 1, L3824: 1,H0520: 1, H0593: 1, H0682: 1, H0670: 1, H0672: 1, H0539: 1, L3833: 1,S0044: 1, H0626: 1, H0732: 1, S3012: 1, S3014: 1, S0027: 1, S0028: 1,L0779: 1, L0584: 1, L0608: 1, L0593: 1, H0667: 1 and H0542: 1. 170HRADN25 800628 180 198-395 AR277: 30, AR283: 24, AR104: 22, AR219: 21,AR316: 20, AR282: 18, AR218: 18, AR089: 17, AR313: 17, AR096: 17, AR240:16, AR299: 14, AR185: 14, AR300: 13, AR060: 12, AR039: 12, AR055: 12,H0556: 10, H0618: 6, H0253: 6, L0748: 6, L0758: 6, H0305: 5, L0742: 5,H0038: 4, L0439: 4, L0592: 3, H0013: 2, H0194: 2, H0545: 2, H0009: 2,H0014: 2, H0617: 2, H0087: 2, L0769: 2, L0774: 2, L0776: 2, L0665: 2,L0438: 2, H0690: 2, H0539: 2, S0380: 2, L0747: 2, L0779: 2, H0265: 1,H0657: 1, S0420: 1, S0376: 1, H0734: 1, S0278: 1, H0455: 1, H0333: 1,H0632: 1, H0581: 1, S0049: 1, H0052: 1, H0123: 1, S0362: 1, H0687: 1,H0688: 1, H0606: 1, H0673: 1, H0135: 1, H0090: 1, H0591: 1, H0040: 1,H0616: 1, S0438: 1, S0142: 1, L0638: 1, L4747: 1, L0796: 1, L5565: 1,L0761: 1, L0643: 1, L0645: 1, L0662: 1, L0768: 1, L0794: 1, L0775: 1,L0375: 1, L0378: 1, L0655: 1, L0382: 1, L0793: 1, L0666: 1, L0663: 1,S0053: 1, S0374: 1, H0547: 1, H0658: 1, H0660: 1, H0651: 1, H0521: 1,S0406: 1, H0555: 1, H0436: 1, S0390: 1, S3014: 1, S0027: 1, L0743: 1,L0777: 1, L0731: 1, H0707: 1, S0436: 1, H0543: 1 and H0422: 1. 171HRDDQ39 840405 181 215-355 AR313: 36, AR039: 33, AR185: 27, AR299: 20,AR089: 18, AR300: 17, AR096: 17, AR240: 16, AR218: 15, AR277: 14, AR316:13, AR060: 11, AR219: 10, AR104: 9, AR055: 8, AR282: 7, AR283: 7, S0001:2, H0436: 2, S0134: 1, H0657: 1, H0441: 1, H0009: 1, H0123: 1, H0050: 1,H0428: 1, H0124: 1, H0529: 1, H0521: 1 and H0352: 1. 172 HRDER22 688056182 32-61 AR283: 14, AR104: 12, AR296: 12, AR289: 11, AR298: 11, AR060:11, AR089: 10, AR291: 10, AR284: 10, AR292: 10, AR266: 10, AR286: 10,AR055: 9, AR270: 9, AR285: 9, AR282: 9, AR247: 9, AR294: 8, AR033: 8,AR293: 8, AR243: 8, AR277: 8, AR263: 8, AR238: 8, AR183: 8, AR240: 8,AR295: 8, AR299: 8, AR241: 8, AR269: 7, AR281: 7, AR316: 7, AR185: 7,AR192: 7, AR182: 7, AR194: 7, AR218: 7, AR177: 7, AR290: 7, AR184: 7,AR061: 7, AR186: 7, AR267: 7, AR219: 6, AR246: 6, AR175: 6, AR202: 6,AR204: 6, AR274: 6, AR268: 6, AR229: 6, AR206: 6, AR096: 6, AR251: 6,AR234: 6, AR256: 6, AR232: 6, AR300: 6, AR198: 5, AR313: 5, AR039: 5,AR273: 5, AR205: 5, AR259: 5, AR227: 5, AR275: 5, AR310: 5, AR052: 5,AR258: 5, AR233: 5, AR226: 5, AR312: 4, AR237: 4, AR271: 4, AR248: 4,AR309: 4, AR253: 4, AR053: 4, AR244: 4, AR280: 4, AR231: 4, AR213: 4,AR315: 4, AR179: 3, AR249: 3, AR265: 3, AR314: 2, L0769: 5, L0751: 5,L0770: 4, L0758: 3, H0716: 2, H0617: 2, L0771: 2, L0803: 2, L0806: 2,L0809: 2, L0789: 2, L0740: 2, L0779: 2, L0600: 2, H0402: 1, S0420: 1,L0005: 1, S0442: 1, S0360: 1, H0637: 1, H0728: 1, H0261: 1, S0222: 1,H0370: 1, H0392: 1, H0438: 1, H0592: 1, H0586: 1, L0622: 1, L0623: 1,H0427: 1, L0021: 1, H0575: 1, H0618: 1, H0581: 1, H0123: 1, H0012: 1,H0039: 1, H0424: 1, S0364: 1, H0124: 1, H0087: 1, H0412: 1, L0800: 1,L0648: 1, L0662: 1, L0774: 1, L0805: 1, L0657: 1, L0658: 1, L0542: 1,L5623: 1, L0788: 1, L0666: 1, L0665: 1, L3825: 1, H0547: 1, H0521: 1,S0406: 1, H0576: 1, L0742: 1, L0777: 1 and L0366: 1. 173 HRDEX93 816046183 649-867 AR104: 30, AR218: 25, AR219: 24, AR240: 22, AR096: 21,AR185: 17, AR039: 16, AR316: 16, AR313: 16, AR055: 14, AR060: 14, AR299:13, AR089: 13, AR282: 9, AR277: 9, AR300: 9, AR283: 6, H0694: 12, L0748:10, L0731: 7, L0754: 6, H0556: 5, L0758: 5, H0265: 4, S0420: 4, S0408:4, L0517: 4, H0657: 3, H0618: 3, H0052: 3, H0083: 3, H0553: 3, H0494: 3,L0763: 3, L0666: 3, L0663: 3, S0126: 3, L0747: 3, H0295: 2, S0134: 2,S0418: 2, H0637: 2, S0046: 2, H0431: 2, H0545: 2, H0014: 2, H0271: 2,H0039: 2, H0424: 2, H0124: 2, H0641: 2, L0764: 2, L0766: 2, L0774: 2,L0775: 2, L0776: 2, L0655: 2, L0783: 2, L0665: 2, H0519: 2, H0522: 2,S0044: 2, L0755: 2, S0436: 2, L0595: 2, L0362: 2, H0543: 2, S0040: 1,H0740: 1, H0656: 1, S0212: 1, H0484: 1, H0661: 1, H0662: 1, S0360: 1,H0733: 1, H0619: 1, S0222: 1, H0486: 1, H0156: 1, H0575: 1, H0706: 1,H0253: 1, S0010: 1, S0346: 1, H0318: 1, H0596: 1, H0231: 1, H0046: 1,H0150: 1, H0081: 1, H0050: 1, H0012: 1, H0620: 1, L0163: 1, S0051: 1,T0010: 1, S6028: 1, H0266: 1, H0179: 1, H0292: 1, H0031: 1, H0644: 1,H0182: 1, H0617: 1, H0606: 1, H0673: 1, L0455: 1, L0456: 1, H0598: 1,H0038: 1, H0040: 1, H0616: 1, H0087: 1, T0067: 1, H0264: 1, T0041: 1,H0131: 1, H0647: 1, S0002: 1, L0772: 1, L0642: 1, L0662: 1, L0767: 1,L0657: 1, L0659: 1, L0382: 1, L5623: 1, L0664: 1, S0374: 1, H0593: 1,H0690: 1, H0682: 1, H0659: 1, H0658: 1, H0666: 1, H0651: 1, H0539: 1,H0521: 1, S0406: 1, H0576: 1, L0743: 1, L0740: 1, L0750: 1, L0779: 1 andH0445: 1. 174 HRDFK37 840381 184 120-152 H0556: 4, L0731: 3, H0124: 2,L0766: 2, L0809: 2, L0747: 2, L0603: 2, S0218: 1, H0657: 1, S0116: 1,H0549: 1, H0550: 1, H0250: 1, H0253: 1, H0052: 1, H0083: 1, H0355: 1,L0483: 1, H0181: 1, H0617: 1, H0032: 1, S0364: 1, H0264: 1, H0100: 1,H0494: 1, L0065: 1, L0770: 1, L0769: 1, L0772: 1, L0764: 1, L0662: 1,L0768: 1, L0387: 1, L0657: 1, L0658: 1, L0541: 1, S0052: 1, S0374: 1,L0565: 1, H0547: 1, S0406: 1, H0478: 1, L0740: 1, L0779: 1, L0757: 1,L0759: 1, H0444: 1, H0445: 1, L0592: 1 and L0595: 1. 175 HRTAP63 780698185  959-1087 AR219: 53, AR218: 46, AR313: 33, AR104: 28, AR096: 26,AR089: 25, AR316: 24, AR039: 20, AR299: 19, AR185: 18, AR300: 17, AR060:17, AR282: 16, AR055: 15, AR240: 13, AR277: 10, AR283: 9, S0474: 28,H0521: 15, L0758: 14, L0752: 13, L0731: 13, L0755: 10, H0641: 9, L0766:8, H0179: 6, L0748: 6, L0439: 6, L0759: 6, H0638: 5, S0222: 5, H0581: 5,L0662: 5, L0655: 5, H0436: 5, L0740: 5, L0777: 5, S0436: 5, H0457: 4,L0775: 4, L0809: 4, H0522: 4, L0742: 4, L0754: 4, L0747: 4, L0749: 4,L0750: 4, L0757: 4, H0580: 3, H0619: 3, H0052: 3, S0003: 3, H0038: 3,H0623: 3, L0666: 3, L0663: 3, S0053: 3, S0126: 3, S0434: 3, S0026: 3,S0212: 2, S0442: 2, S0408: 2, H0747: 2, S0476: 2, H0156: 2, L0021: 2,H0599: 2, S0010: 2, H0014: 2, S0214: 2, H0031: 2, H0644: 2, H0628: 2,S0036: 2, H0090: 2, H0616: 2, S0144: 2, S0002: 2, L0598: 2, L0764: 2,L0768: 2, L0774: 2, L0806: 2, L0653: 2, L0657: 2, L0659: 2, H0520: 2,H0547: 2, H0539: 2, H0710: 2, S0027: 2, L0779: 2, L0588: 2, L0592: 2,L0594: 2, L0366: 2, H0665: 2, H0739: 1, H0170: 1, T0002: 1, S0342: 1,H0717: 1, H0740: 1, S0114: 1, S0218: 1, H0650: 1, H0657: 1, S0282: 1,L3659: 1, S0418: 1, S0420: 1, L0005: 1, T0008: 1, H0742: 1, H0722: 1,H0735: 1, S0007: 1, S0046: 1, H0749: 1, L3388: 1, H0351: 1, H0406: 1,S0278: 1, H0461: 1, H0601: 1, H0586: 1, H0497: 1, H0574: 1, T0039: 1,L3655: 1, H0013: 1, H0427: 1, H0575: 1, H0590: 1, H0421: 1, S0049: 1,H0327: 1, H0545: 1, H0046: 1, H0572: 1, H0570: 1, H0050: 1, L0471: 1,H0373: 1, H0510: 1, H0375: 1, S6028: 1, H0266: 1, H0271: 1, H0719: 1,H0416: 1, S0340: 1, S0312: 1, H0615: 1, L0483: 1, T0006: 1, H0169: 1,H0674: 1, H0163: 1, H0591: 1, H0551: 1, H0264: 1, H0412: 1, H0059: 1,H0494: 1, S0015: 1, S0344: 1, UNKWN: 1, H0529: 1, L0520: 1, L0637: 1,L0761: 1, L0667: 1, L0772: 1, L0641: 1, L0648: 1, L0521: 1, L0794: 1,L0649: 1, L0803: 1, L0805: 1, L0783: 1, L0384: 1, L5622: 1, L0793: 1,L0664: 1, L0665: 1, S0052: 1, S0428: 1, S0216: 1, H0144: 1, L3811: 1,H0658: 1, H0670: 1, H0666: 1, H0672: 1, H0651: 1, L0355: 1, S0328: 1,S0152: 1, H0696: 1, S0406: 1, H0555: 1, S0028: 1, S0032: 1, L0744: 1,L0745: 1, L0780: 1, L0362: 1, H0422: 1 and H0721: 1. 176 HSAVA08 580870186  66-146 AR313: 39, AR039: 39, AR299: 18, AR089: 17, AR096: 17,AR185: 16, AR277: 16, AR300: 16, AR104: 12, AR316: 12, AR240: 10, AR219:10, AR218: 9, AR060: 9, AR282: 9, AR055: 8, AR283: 5, S0114: 2 177HSAVW42 637660 187 129-197 AR277: 28, AR283: 24, AR219: 20, AR055: 17,AR218: 16, AR316: 16, AR282: 16, AR313: 15, AR089: 15, AR104: 13, AR299:12, AR185: 11, AR240: 11, AR096: 11, AR039: 10, AR300: 9, AR060: 8,H0412: 2, S0114: 1, S0222: 1, H0169: 1, L0520: 1, L0805: 1, L0776: 1,L0750: 1 and L0777: 1. 178 HSAYC41 688057 188 106-213 S0114: 1, H0411:1, H0179: 1, L0665: 1 and H0435: 1. 179 HSDZM54 637870 189 445-552AR060: 424, AR055: 413, AR299: 314, AR185: 295, AR277: 232, AR104: 224,AR283: 216, AR089: 202, AR282: 188, AR300: 180, AR039: 167, AR316: 159,AR240: 126, AR096: 104, AR219: 88, AR218: 76, AR313: 63, H0455: 1 180HSHBF76 715838 190 129-161 L0747: 7, H0599: 5, H0622: 4, L0764: 4,L0794: 4, L0659: 4, L0005: 3, H0144: 3, L0749: 3, L0750: 3, S0046: 2,H0013: 2, H0046: 2, H0031: 2, L0770: 2, L0761: 2, L0649: 2, L0806: 2,L0809: 2, L0744: 2, L0754: 2, L0755: 2, L0588: 2, L0603: 2, H0171: 1,H0685: 1, S0212: 1, S0376: 1, S0132: 1, H0645: 1, H0619: 1, S6022: 1,H0574: 1, L0738: 1, L0157: 1, H0030: 1, H0135: 1, H0616: 1, H0494: 1,L0800: 1, L0771: 1, L0773: 1, L0662: 1, L0803: 1, L0783: 1, L0789: 1,L0665: 1, S0374: 1, H0539: 1, S3012: 1, S0037: 1, S0027: 1, L0751: 1,L0756: 1, L0779: 1, L0731: 1, L0758: 1, H0653: 1 and H0352: 1. 181HSIFG47 778378 191 304-345 H0590: 1 182 HSJBY32 702020 192 257-532AR055: 3, AR300: 3, AR277: 3, AR299: 2, AR060: 2, AR185: 2, AR039: 2,AR104: 2, AR282: 1, AR283: 1, AR240: 1, AR096: 1, AR316: 1, AR089: 1,H0729: 1, H0735: 1, S0222: 1, H0271: 1, L0796: 1, L0766: 1, S0032: 1 andL0747: 1. 183 HSKDR27 580874 193 473-556 AR055: 9, AR104: 9, AR218: 7,AR060: 7, AR299: 6, AR185: 6, AR039: 6, AR240: 5, AR089: 5, AR219: 5,AR300: 5, AR283: 5, AR316: 4, AR313: 4, AR096: 3, AR277: 3, AR282: 2,S0027: 95, S0192: 54, S3014: 53, S0126: 42, S0040: 35, H0424: 23, S0028:22, S0037: 19, S3012: 16, H0213: 13, T0006: 12, H0250: 11, S0032: 11,L0744: 11, T0040: 10, H0124: 10, H0429: 10, L0740: 10, L0588: 10, L0754:9, H0545: 8, H0280: 8, S0194: 8, S0196: 7, H0392: 6, T0039: 6, H0150: 6,H0039: 6, S0206: 6, L0743: 6, L0731: 6, S0342: 5, S0212: 5, S0045: 5,H0486: 5, H0575: 5, H0014: 5, H0090: 5, H0551: 5, H0100: 5, S0044: 5,S0011: 5, H0255: 4, H0318: 4, H0271: 4, S0022: 4, H0031: 4, H0181: 4,H0032: 4, H0038: 4, T0067: 4, S0124: 4, L0747: 4, L0749: 4, H0402: 3,H0309: 3, H0046: 3, S0250: 3, H0068: 3, H0087: 3, H0059: 3, S0142: 3,S0053: 3, H0419: 2, S0116: 2, S0408: 2, S0132: 2, S0278: 2, S0222: 2,H0331: 2, T0060: 2, H0069: 2, H0427: 2, H0599: 2, T0082: 2, H0253: 2,H0546: 2, H0086: 2, H0123: 2, H0024: 2, H0015: 2, H0510: 2, H0428: 2,T0023: 2, H0163: 2, H0063: 2, H0509: 2, L0772: 2, L0805: 2, S0052: 2,H0547: 2, H0518: 2, L0748: 2, L0751: 2, L0745: 2, L0750: 2, L0777: 2,L0755: 2, L0757: 2, H0445: 2, L0590: 2, L0599: 2, S0026: 2, S0242: 2,H0171: 1, H0265: 1, H0716: 1, H0294: 1, S0298: 1, H0662: 1, H0450: 1,S0360: 1, H0329: 1, S0046: 1, H0411: 1, S6022: 1, H0431: 1, H0357: 1,H0455: 1, H0586: 1, H0587: 1, L0021: 1, H0042: 1, T0048: 1, H0505: 1,H0052: 1, H0251: 1, H0235: 1, H0231: 1, H0544: 1, H0050: 1, H0051: 1,H0071: 1, H0083: 1, H0060: 1, H0266: 1, H0188: 1, H0292: 1, S0214: 1,H0328: 1, H0033: 1, H0417: 1, H0553: 1, H0628: 1, H0617: 1, H0606: 1,H0383: 1, H0212: 1, H0388: 1, H0135: 1, H0040: 1, H0487: 1, H0413: 1,T0069: 1, H0560: 1, H0538: 1, S0210: 1, L0763: 1, L0646: 1, L0641: 1,L0649: 1, L0803: 1, L0652: 1, L0629: 1, L0659: 1, L0787: 1, L0665: 1,H0435: 1, H0528: 1, H0521: 1, H0555: 1, L0779: 1, L0581: 1, S0276: 1 andH0008: 1. 184 HSNAP85 784054 194 941-955 AR218: 36, AR219: 31, AR313:20, AR089: 16, AR055: 16, AR299: 13, AR185: 13, AR316: 10, AR060: 9,AR104: 8, AR300: 8, AR282: 8, AR096: 7, AR039: 7, AR277: 6, AR283: 5,AR240: 5, L0105: 11, L0754: 10, L0803: 9, L0777: 8, L0740: 6, L0770: 4,L0649: 4, L0805: 4, L0731: 4, S0212: 3, L0766: 3, L0752: 3, L0599: 3,H0265: 2, L3643: 2, H0656: 2, S0418: 2, S0444: 2, S0360: 2, H0581: 2,L0157: 2, T0023: 2, H0038: 2, H0413: 2, S0422: 2, H0529: 2, L0794: 2,L0774: 2, L0654: 2, L0776: 2, L0666: 2, L0663: 2, L0665: 2, H0547: 2,H0696: 2, S0027: 2, L0743: 2, L0744: 2, L0750: 2, L0779: 2, L0759: 2,S0192: 2, S0242: 2, H0624: 1, S0134: 1, H0341: 1, H0663: 1, H0664: 1,H0729: 1, H0722: 1, S0045: 1, S0476: 1, H0619: 1, H0610: 1, H0497: 1,L3816: 1, H0486: 1, H0013: 1, H0575: 1, H0318: 1, H0545: 1, H0569: 1,L0471: 1, H0328: 1, H0615: 1, H0553: 1, H0163: 1, H0040: 1, H0551: 1,H0412: 1, S0370: 1, S0438: 1, L0646: 1, L0521: 1, L0662: 1, L0804: 1,L0775: 1, L0655: 1, L0658: 1, L0634: 1, L0809: 1, S0374: 1, L3824: 1,L3826: 1, H0435: 1, H0660: 1, H0672: 1, S0378: 1, H0754: 1, H0576: 1,S0390: 1, S3014: 1, S0206: 1, L0747: 1, L0758: 1, L0608: 1, S0026: 1,S0194: 1 and H0506: 1. 185 HSNBM34 635131 195 1508-1696 AR185: 18,AR039: 18, AR299: 15, AR104: 11, AR055: 9, AR277: 9, AR060: 8, AR096: 8,AR282: 8, AR300: 7, AR218: 7, AR240: 7, AR313: 6, AR316: 6, AR219: 5,AR283: 4, AR089: 4, H0599: 9, H0144: 8, H0457: 7, H0266: 7, H0494: 6,H0046: 5, H0031: 5, H0553: 5, L5622: 5, H0593: 5, H0521: 5, H0734: 4,H0013: 4, H0135: 4, S0436: 4, S0212: 3, H0069: 3, H0036: 3, H0052: 3,S0022: 3, H0708: 3, H0551: 3, H0696: 3, S0434: 3, H0713: 2, H0717: 2,S0418: 2, S0354: 2, H0580: 2, H0728: 2, H0733: 2, H0550: 2, H0587: 2,H0559: 2, H0706: 2, H0253: 2, H0355: 2, H0039: 2, S0364: 2, H0038: 2,H0634: 2, H0433: 2, H0560: 2, S0440: 2, H0646: 2, L3818: 2, S0002: 2,L0506: 2, L5623: 2, H0547: 2, S0126: 2, H0518: 2, H0436: 2, H0478: 2,S3014: 2, L0601: 2, H0506: 2, H0265: 1, H0556: 1, T0002: 1, S0114: 1,H0583: 1, S0116: 1, S0356: 1, S0442: 1, S0358: 1, S0376: 1, S0360: 1,S0408: 1, H0340: 1, H0742: 1, H0735: 1, S0132: 1, S0476: 1, H0619: 1,S0278: 1, S0222: 1, H0409: 1, H0602: 1, H0592: 1, H0586: 1, H0486: 1,H0270: 1, S0280: 1, H0042: 1, H0575: 1, H0122: 1, H0590: 1, S0010: 1,T0048: 1, H0318: 1, S0474: 1, S0049: 1, H0173: 1, H0085: 1, H0597: 1,H0231: 1, H0327: 1, H0544: 1, H0123: 1, H0050: 1, H0095: 1, H0373: 1,L0163: 1, H0051: 1, T0010: 1, T0023: 1, H0213: 1, L0142: 1, H0383: 1,S0366: 1, H0163: 1, H0040: 1, H0616: 1, H0087: 1, H0379: 1, S0038: 1,T0042: 1, S0150: 1, S0144: 1, H0529: 1, L0369: 1, L3905: 1, L0766: 1,L0775: 1, L0532: 1, H0693: 1, H0689: 1, H0670: 1, L0602: 1, H0522: 1,S0044: 1, L0611: 1, S0027: 1, S0028: 1, L0741: 1, L0743: 1, L0748: 1,L0439: 1, L0592: 1, L0485: 1, L0608: 1, L0366: 1, H0668: 1, H0542: 1,H0543: 1 and H0423: 1. 186 HSQDO85 853393 196 133-168 AR219: 50, AR218:47, AR096: 37, AR316: 34, AR313: 28, AR039: 27, AR299: 25, AR277: 22,AR185: 21, AR282: 21, AR089: 21, AR300: 20, AR240: 19, AR104: 18, AR283:17, AR055: 16, AR060: 15, S0026: 1 187 HSRBE06 871264 197 128-193 AR313:33, AR039: 26, AR299: 17, AR277: 15, AR096: 14, AR089: 14, AR300: 13,AR185: 12, AR316: 11, AR282: 10, AR218: 9, AR240: 9, AR104: 9, AR219: 7,AR060: 7, AR055: 5, AR283: 4, S0011: 3, H0306: 1, H0402: 1, L0004: 1,H0486: 1, H0050: 1, S0051: 1, H0494: 1 and S0002: 1. 188 HSSDI26 560722198 253-318 AR313: 14, AR039: 11, AR299: 9, AR185: 8, AR089: 8, AR277:8, AR300: 7, AR218: 6, AR060: 6, AR240: 6, AR055: 6, AR096: 6, AR316: 5,AR104: 5, AR283: 4, AR282: 4, AR219: 3, H0135: 1 189 HSSEA64 853395 199 58-246 AR240: 12, AR055: 11, AR060: 10, AR277: 9, AR282: 9, AR089: 9,AR096: 8, AR218: 8, AR283: 7, AR219: 7, AR104: 6, AR300: 6, AR185: 6,AR316: 6, AR299: 5, AR039: 5, AR313: 4, H0052: 17, L0745: 11, L0748: 10,L0777: 8, L0755: 8, H0547: 7, L0439: 7, L0766: 6, L0774: 6, L0771: 5,L0662: 4, L0746: 4, S0474: 3, L0163: 3, H0059: 3, H0100: 3, L0770: 3,L0775: 3, L0665: 3, L0741: 3, L0751: 3, L0758: 3, L0759: 3, H0261: 2,H0333: 2, H0618: 2, H0194: 2, H0545: 2, H0012: 2, H0617: 2, H0135: 2,L0763: 2, L0769: 2, L0768: 2, L0657: 2, L0438: 2, H0520: 2, H0539: 2,S0152: 2, L0747: 2, L0752: 2, L0753: 2, S0436: 2, L0588: 2, S0040: 1,T0049: 1, H0657: 1, H0663: 1, S0420: 1, S0358: 1, S0360: 1, H0675: 1,H0645: 1, L0717: 1, H0437: 1, H0550: 1, S6016: 1, H0497: 1, H0574: 1,H0599: 1, H0575: 1, H0253: 1, H0041: 1, H0620: 1, H0373: 1, H0375: 1,H0188: 1, H0181: 1, H0124: 1, H0068: 1, H0040: 1, H0561: 1, S0448: 1,S0440: 1, S0210: 1, S0002: 1, L0638: 1, L0639: 1, L0627: 1, L0644: 1,L0773: 1, L0767: 1, L0387: 1, L0375: 1, L0651: 1, L0806: 1, L0776: 1,L0659: 1, L0540: 1, L5622: 1, L2261: 1, H0144: 1, H0593: 1, S0126: 1,H0694: 1, H0134: 1, H0555: 1, S0390: 1, S0028: 1, L0749: 1, L0786: 1,L0780: 1, L0731: 1, L0757: 1, L0605: 1, L0592: 1, S0026: 1 and S0276: 1.190 HSSEF77 658725 200 184-366 H0617: 7, L0750: 7, H0556: 5, L0769: 5,L0783: 5, L0758: 5, L0759: 5, L0665: 4, L0741: 4, S0132: 3, L0761: 3,L0742: 3, L0439: 3, L0755: 3, L0592: 3, H0618: 2, H0620: 2, H0038: 2,L0771: 2, L0662: 2, L0659: 2, L0666: 2, S0126: 2, H0670: 2, S0328: 2,S0380: 2, L0747: 2, L0753: 2, L0731: 2, H0395: 1, H0295: 1, H0294: 1,H0657: 1, H0656: 1, H0341: 1, H0484: 1, H0663: 1, H0638: 1, S0356: 1,S0444: 1, H0741: 1, L3271: 1, H0549: 1, H0550: 1, H0370: 1, H0455: 1,H0632: 1, H0486: 1, T0039: 1, T0112: 1, H0156: 1, H0581: 1, H0052: 1,H0545: 1, H0046: 1, H0150: 1, H0081: 1, S0051: 1, H0107: 1, H0061: 1,H0188: 1, H0288: 1, S0250: 1, H0428: 1, H0135: 1, H0163: 1, H0090: 1,H0616: 1, T0004: 1, S0438: 1, L0770: 1, L0796: 1, L0637: 1, L0772: 1,L0372: 1, L0646: 1, L0521: 1, L0768: 1, L0766: 1, L5574: 1, L0774: 1,L0775: 1, L0375: 1, L0806: 1, L0776: 1, L0807: 1, L0657: 1, L0658: 1,L0540: 1, L0384: 1, L0809: 1, L0663: 1, L0438: 1, H0672: 1, H0754: 1,S0188: 1, S0406: 1, H0436: 1, H0576: 1, S3014: 1, L0748: 1, L0779: 1,L0757: 1 and H0506: 1. 191 HSSFE38 742512 201 264-641 AR218: 169, AR219:154, AR240: 64, AR185: 42, AR096: 42, AR039: 40, AR055: 36, AR316: 29,AR104: 24, AR299: 23, AR089: 21, AR060: 18, AR313: 17, AR283: 14, AR300:14, AR282: 10, AR277: 8 192 HSXCP38 895392 202 211-255 AR104: 7, AR055:5, AR060: 4, AR039: 2, AR185: 2, AR240: 2, AR089: 2, AR282: 2, AR277: 2,AR316: 2, AR299: 2, AR313: 2, AR300: 2, AR283: 1, AR218: 1, AR096: 1,L0439: 3, L3655: 1, H0050: 1, T0010: 1, S0036: 1, L0438: 1 and L0759: 1.193 HT1SC27 630647 203 366-449 AR313: 10, AR039: 9, AR219: 9, AR218: 8,AR185: 7, AR055: 7, AR060: 6, AR089: 6, AR299: 6, AR277: 5, AR282: 5,AR316: 5, AR096: 5, AR240: 4, AR104: 4, AR300: 4, AR283: 3, H0218: 20,H0219: 7, H0157: 3, H0207: 2, H0169: 1, S0440: 1 and L0749: 1. 194HT4FV41 853400 204  39-452 AR244: 10, AR185: 10, AR204: 9, AR275: 9,AR202: 9, AR194: 9, AR052: 9, AR271: 8, AR246: 8, AR289: 8, AR219: 7,AR316: 7, AR104: 7, AR198: 7, AR089: 7, AR277: 7, AR310: 7, AR060: 7,AR309: 7, AR206: 7, AR039: 7, AR229: 7, AR282: 7, AR053: 7, AR283: 7,AR269: 6, AR205: 6, AR270: 6, AR312: 6, AR184: 6, AR186: 6, AR299: 6,AR096: 6, AR240: 6, AR251: 6, AR274: 6, AR182: 6, AR055: 6, AR033: 6,AR291: 6, AR218: 6, AR243: 6, AR266: 6, AR290: 6, AR192: 5, AR268: 5,AR280: 5, AR247: 5, AR213: 5, AR298: 5, AR231: 5, AR273: 5, AR313: 5,AR234: 5, AR284: 5, AR296: 5, AR061: 5, AR248: 5, AR238: 5, AR285: 5,AR183: 5, AR253: 5, AR300: 5, AR267: 4, AR286: 4, AR315: 4, AR175: 4,AR293: 4, AR294: 4, AR177: 4, AR249: 4, AR281: 3, AR227: 3, AR233: 3,AR292: 3, AR263: 3, AR265: 3, AR232: 3, AR295: 3, AR226: 3, AR237: 3,AR258: 2, AR314: 2, AR256: 1, AR259: 1, AR179: 1, AR241: 1, L0794: 10,L0800: 7, L0769: 6, L0751: 6, L0761: 4, L0809: 4, H0521: 4, L0439: 4,H0585: 3, H0617: 3, H0494: 3, L0659: 3, L0665: 3, L0777: 3, H0265: 2,H0255: 2, S0354: 2, S0376: 2, H0370: 2, H0069: 2, H0083: 2, H0040: 2,L0770: 2, L0764: 2, L0662: 2, L5622: 2, L0666: 2, L0663: 2, L0438: 2,L0743: 2, L0780: 2, S0436: 2, H0667: 2, H0423: 2, S0040: 1, H0713: 1,H0295: 1, H0254: 1, H0638: 1, S0418: 1, S0420: 1, S0360: 1, H0734: 1,S0046: 1, S0476: 1, H0587: 1, H0635: 1, H0575: 1, H0004: 1, H0618: 1,H0052: 1, H0194: 1, H0544: 1, H0545: 1, H0373: 1, T0010: 1, H0267: 1,H0179: 1, H0622: 1, L0194: 1, H0181: 1, H0124: 1, H0087: 1, H0412: 1,H0413: 1, H0646: 1, S0144: 1, L0369: 1, L0640: 1, L0763: 1, L0772: 1,L0646: 1, L0643: 1, L0644: 1, L0768: 1, L0803: 1, L0805: 1, L0655: 1,L0518: 1, L0783: 1, L0384: 1, L0789: 1, S0052: 1, L2263: 1, L0710: 1,H0547: 1, H0682: 1, S0152: 1, H0187: 1, H0727: 1, S0390: 1, L0752: 1,L0757: 1, L0758: 1, H0665: 1, H0543: 1, H0422: 1 and S0424: 1. 195HT5GR59 801930 205 135-230 AR240: 19, AR096: 15, AR316: 10, AR300: 9,AR055: 9, AR039: 8, AR313: 8, AR282: 8, AR277: 7, AR185: 7, AR060: 7,AR219: 7, AR218: 6, AR299: 6, AR104: 6, AR283: 6, AR089: 5, H0584: 36,H0585: 22, H0141: 11, H0167: 9, H0457: 7, H0521: 6, S0474: 4, H0575: 3,L0731: 3, H0265: 2, H0556: 2, H0581: 2, L0761: 2, H0543: 2, H0140: 1,H0638: 1, S0358: 1, S0140: 1, H0747: 1, H0619: 1, H0497: 1, H0559: 1,H0069: 1, H0635: 1, H0427: 1, S0280: 1, H0252: 1, H0477: 1, L0667: 1,L0768: 1, L0775: 1, L0659: 1, L0791: 1, L0792: 1, S0053: 1, L0777: 1,L0758: 1, H0445: 1 and H0506: 1. 196 HTEAG62 812332 206 1017-1085 AR310:2, AR282: 2, AR206: 2, AR273: 2, AR186: 1, AR295: 1, AR294: 1, AR175: 1,L0766: 6, H0038: 5, L0758: 4, H0616: 3, S0422: 2, L0779: 2, L0752: 2,H0638: 1, S0376: 1, S0132: 1, L3388: 1, H0250: 1, L0564: 1, L0794: 1,L0803: 1, L0666: 1, L0777: 1, L0755: 1, H0595: 1, S0434: 1 and H0542: 1.197 HTEEW69 764835 207  182-1153 AR104: 36, AR283: 28, AR219: 27, AR218:27, AR316: 21, AR277: 20, AR089: 20, AR055: 19, AR096: 18, AR313: 18,AR240: 18, AR282: 18, AR185: 16, AR299: 16, AR060: 15, AR039: 14, AR300:12, H0038: 8, H0616: 4, L0779: 3, L0758: 3, L0753: 2, L0032: 1, T0006:1, H0040: 1, L0768: 1 and H0547: 1. 198 HTEGS07 827700 208 493-606AR283: 22, AR277: 9, AR055: 8, AR218: 8, AR219: 7, AR060: 6, AR104: 6,AR300: 6, AR282: 5, AR240: 5, AR039: 4, AR089: 4, AR316: 4, AR185: 4,AR299: 4, AR096: 4, AR313: 3, L0804: 2, L0747: 2, L0485: 2, L0604: 2,L0623: 1, H0708: 1, S0366: 1, H0038: 1, L0794: 1, L0775: 1 and L0779: 1.199 HTEGS11 862066 209 173-196 AR219: 12, AR055: 9, AR218: 9, AR185: 9,AR060: 8, AR300: 7, AR240: 6, AR104: 6, AR089: 6, AR282: 6, AR299: 6,AR096: 5, AR039: 5, AR316: 4, AR313: 3, AR283: 3, AR277: 3, L0748: 8,L0598: 4, L0747: 4, L0770: 3, L0750: 3, L0756: 3, H0645: 2, H0619: 2,L0794: 2, L0666: 2, L0439: 2, L0749: 2, L0777: 2, L0731: 2, H0170: 1,S0040: 1, H0713: 1, H0486: 1, H0196: 1, L0471: 1, H0038: 1, L0769: 1,L0637: 1, L0761: 1, L0772: 1, L0766: 1, L0775: 1, L0367: 1, L0789: 1,L0793: 1, H0144: 1, H0547: 1, L0758: 1 and L0581: 1. 200 HTEHU59 840385210 170-274 AR313: 11, AR218: 10, AR219: 9, AR039: 7, AR316: 6, AR096:6, AR104: 6, AR277: 5, AR299: 5, AR055: 5, AR282: 4, AR089: 4, AR283: 3,AR300: 3, AR060: 3, AR240: 3, AR185: 3, S0422: 6, H0038: 4, L0758: 4,L0754: 3, S0360: 2, H0024: 2, L0598: 2, L0766: 2, L0748: 2, L0747: 2,L0756: 2, H0583: 1, H0341: 1, S0418: 1, L0005: 1, H0741: 1, H0437: 1,H0369: 1, H0581: 1, H0194: 1, S0050: 1, H0271: 1, H0428: 1, T0006: 1,H0068: 1, H0412: 1, H0056: 1, H0494: 1, S0426: 1, L0772: 1, L0646: 1,L0662: 1, L0803: 1, L0806: 1, L0776: 1, L0655: 1, L0789: 1, L0792: 1,H0144: 1, S0374: 1, H0670: 1, H0627: 1, S0026: 1 and S0192: 1. 201HTEJD29 695798 211 101-172 H0038: 2 202 HTEKM46 862069 212 171-287S0422: 6, H0038: 4, L0758: 4, L0754: 3, S0360: 2, H0024: 2, L0598: 2,L0766: 2, L0748: 2, L0747: 2, L0756: 2, H0583: 1, H0341: 1, S0418: 1,L0005: 1, H0741: 1, H0437: 1, H0369: 1, H0581: 1, H0194: 1, S0050: 1,H0271: 1, H0428: 1, T0006: 1, H0068: 1, H0412: 1, H0056: 1, H0494: 1,S0426: 1, L0772: 1, L0646: 1, L0662: 1, L0803: 1, L0806: 1, L0776: 1,L0655: 1, L0789: 1, L0792: 1, H0144: 1, S0374: 1, H0670: 1, H0627: 1,S0026: 1 and S0192: 1. 203 HTENR63 877952 213 132-302 AR277: 32, AR283:29, AR218: 25, AR219: 22, AR282: 21, AR316: 21, AR089: 20, AR313: 19,AR104: 18, AR055: 17, AR299: 16, AR096: 16, AR240: 16, AR185: 15, AR300:14, AR039: 14, AR060: 11, L0748: 9, L0777: 6, L0439: 5, L0749: 5, L0766:4, L0438: 4, L0755: 4, L0752: 3, L0594: 3, L3814: 2, S0212: 2, H0014: 2,H0032: 2, H0598: 2, H0038: 2, H0100: 2, L0775: 2, S0330: 2, L0754: 2,L0750: 2, L0731: 2, L0758: 2, L0759: 2, L0485: 2, S0192: 2, S0040: 1,H0583: 1, S0356: 1, H0733: 1, S0046: 1, H0747: 1, L3652: 1, H0613: 1,H0024: 1, H0373: 1, H0375: 1, H0179: 1, H0166: 1, H0673: 1, H0591: 1,H0616: 1, H0551: 1, H0412: 1, H0129: 1, H0529: 1, L0761: 1, L0771: 1,L0804: 1, L0784: 1, L0806: 1, L0655: 1, L0783: 1, L0666: 1, H0144: 1,L3811: 1, S0126: 1, S0328: 1, H0539: 1, S0152: 1, L0740: 1, L0756: 1,L0779: 1, L0757: 1, H0445: 1, L0599: 1 and S0026: 1. 204 HTGGM44 842856214 179-433 AR246: 5, AR244: 5, AR184: 5, AR253: 5, AR309: 4, AR313: 4,AR186: 4, AR052: 3, AR206: 3, AR312: 3, AR310: 3, AR204: 3, AR274: 3,AR291: 3, AR060: 3, AR055: 3, AR229: 3, AR053: 3, AR292: 3, AR269: 3,AR061: 3, AR243: 3, AR205: 3, AR247: 3, AR213: 2, AR299: 2, AR294: 2,AR089: 2, AR273: 2, AR270: 2, AR266: 2, AR263: 2, AR039: 2, AR265: 2,AR293: 2, AR316: 2, AR275: 2, AR282: 2, AR267: 2, AR251: 2, AR277: 2,AR231: 2, AR283: 2, AR238: 2, AR284: 2, AR185: 2, AR271: 2, AR300: 2,AR182: 2, AR226: 2, AR096: 1, AR237: 1, AR033: 1, AR234: 1, AR290: 1,AR240: 1, AR241: 1, AR259: 1, AR194: 1, AR227: 1, AR104: 1, AR298: 1,L0748: 8, L0805: 2, L0599: 2, S0218: 1, T0040: 1, H0635: 1, S0250: 1,H0212: 1, H0634: 1, H0063: 1, S0002: 1, L0766: 1, H0144: 1, S0126: 1 andH0518: 1. 205 HTHBZ06 832477 215 318-323 AR218: 86, AR219: 83, AR089:54, AR104: 50, AR282: 48, AR313: 44, AR283: 40, AR055: 34, AR316: 31,AR240: 29, AR185: 27, AR096: 23, AR060: 22, AR299: 22, AR300: 16, AR039:15, AR277: 11, S0414: 9, L0005: 7, L0065: 7, S0360: 6, S0422: 5, H0545:4, H0648: 4, L0777: 4, L0758: 4, H0716: 3, H0657: 3, S0474: 3, L0770: 3,L0666: 3, L0665: 3, L0600: 3, H0674: 2, H0494: 2, L0769: 2, L0638: 2,L0637: 2, L0768: 2, L0803: 2, L0774: 2, L0805: 2, L0664: 2, L0438: 2,H0520: 2, H0696: 2, L0751: 2, L0745: 2, L0749: 2, L0756: 2, L0779: 2,L0757: 2, L3643: 1, H0484: 1, H0671: 1, S0358: 1, L3649: 1, H0742: 1,H0741: 1, S0132: 1, L0623: 1, H0581: 1, S0214: 1, H0063: 1, H0412: 1,H0413: 1, S0002: 1, L0369: 1, L0796: 1, L0662: 1, L0766: 1, L0375: 1,L0656: 1, L0659: 1, L0647: 1, L3872: 1, L0663: 1, H0684: 1, S0328: 1,S0350: 1, H0436: 1, L0743: 1, L0754: 1, L0755: 1, L0731: 1, S0031: 1,S0436: 1, L0485: 1, L0608: 1, L0362: 1, H0506: 1 and H0352: 1. 206HTLAP64 603913 216 173-235 AR313: 19, AR039: 14, AR299: 12, AR055: 10,AR185: 9, AR316: 8, AR104: 7, AR096: 7, AR300: 6, AR089: 6, AR060: 5,AR218: 5, AR282: 4, AR283: 4, AR277: 4, AR219: 3, AR240: 3, L0803: 7,L0756: 6, S0422: 4, L0794: 4, L0809: 4, L0754: 4, L0758: 3, S0003: 2,H0615: 2, L0764: 2, L0375: 2, L0659: 2, L0783: 2, L0665: 2, L0748: 2,L0731: 2, L0759: 2, L3643: 1, H0686: 1, S6024: 1, L0002: 1, H0662: 1,L0005: 1, L3649: 1, H0734: 1, H0749: 1, H0441: 1, H0574: 1, L3653: 1,H0575: 1, H0253: 1, S0474: 1, H0052: 1, H0569: 1, H0081: 1, L0471: 1,H0266: 1, H0687: 1, H0622: 1, L0483: 1, H0628: 1, H0606: 1, H0135: 1,H0591: 1, H0059: 1, L0763: 1, L0637: 1, L3904: 1, L0772: 1, L0643: 1,L0768: 1, L0364: 1, L0649: 1, L0774: 1, L4558: 1, L0368: 1, L4501: 1,L0663: 1, L0664: 1, L2655: 1, H0144: 1, L0352: 1, H0519: 1, H0593: 1,S0126: 1, H0660: 1, H0666: 1, H0696: 1, S0406: 1, S0028: 1, L0740: 1,L0745: 1, L0747: 1, L0750: 1, L0779: 1, S0436: 1, L0587: 1, L0597: 1,L0591: 1, S0026: 1, L0097: 1 and S0242: 1. 207 HTLBT80 840045 217 912-1301 AR251: 22, AR273: 18, AR053: 18, AR309: 16, AR310: 16, AR183:15, AR313: 15, AR274: 15, AR263: 15, AR247: 15, AR312: 14, AR314: 14,AR266: 14, AR265: 14, AR219: 14, AR175: 13, AR218: 13, AR285: 12, AR280:12, AR182: 12, AR268: 12, AR293: 12, AR213: 12, AR052: 12, AR292: 11,AR290: 11, AR286: 11, AR267: 11, AR277: 11, AR289: 11, AR315: 11, AR296:11, AR256: 11, AR295: 11, AR177: 10, AR291: 10, AR269: 10, AR271: 10,AR284: 10, AR096: 9, AR243: 9, AR270: 9, AR299: 9, AR283: 9, AR249: 9,AR300: 9, AR033: 9, AR253: 9, AR238: 9, AR184: 8, AR179: 8, AR248: 8,AR231: 8, AR298: 8, AR234: 8, AR061: 8, AR226: 8, AR282: 8, AR232: 8,AR229: 8, AR316: 8, AR258: 8, AR259: 7, AR233: 7, AR240: 7, AR186: 7,AR294: 7, AR185: 7, AR198: 7, AR237: 7, AR275: 6, AR281: 6, AR039: 6,AR192: 6, AR227: 6, AR089: 6, AR104: 6, AR246: 6, AR055: 6, AR244: 6,AR202: 5, AR204: 5, AR060: 5, AR206: 4, AR205: 4, AR241: 4, AR194: 1,L0659: 6, H0556: 4, H0521: 4, L0439: 4, L0745: 4, L0759: 4, H0657: 3,S0360: 3, L0761: 3, L0662: 3, L0766: 3, L0809: 3, H0549: 2, H0392: 2,H0253: 2, H0581: 2, H0620: 2, H0051: 2, H0551: 2, H0494: 2, L0770: 2,L0794: 2, L0649: 2, L0665: 2, H0520: 2, S0032: 2, L0741: 2, L0743: 2,L0748: 2, L0747: 2, L0779: 2, L0758: 2, L0605: 2, H0650: 1, H0484: 1,H0254: 1, H0402: 1, S0358: 1, H0580: 1, H0741: 1, S0007: 1, S0132: 1,S0476: 1, H0393: 1, H0369: 1, H0550: 1, H0409: 1, H0256: 1, H0250: 1,H0042: 1, H0036: 1, H0318: 1, S0049: 1, H0050: 1, H0014: 1, H0375: 1,S6028: 1, H0266: 1, H0292: 1, H0428: 1, H0622: 1, H0031: 1, H0617: 1,L0456: 1, H0135: 1, H0040: 1, H0379: 1, H0264: 1, H0056: 1, H0623: 1,H0100: 1, H0633: 1, S0002: 1, H0529: 1, L0762: 1, L5575: 1, L0772: 1,L0646: 1, L0771: 1, L0773: 1, L0767: 1, L0768: 1, L0803: 1, L0805: 1,L0653: 1, L5622: 1, L4501: 1, L0666: 1, H0689: 1, H0690: 1, H0682: 1,H0670: 1, H0522: 1, S0044: 1, H0436: 1, S0027: 1, L0754: 1, L0749: 1,L0753: 1, L0731: 1, S0436: 1, H0653: 1, S0192: 1, H0542: 1, H0543: 1,H0423: 1 and S0424: 1. 208 HTLDU78 637702 218 219-245 L0758: 3, H0253: 1and L0779: 1. 209 HTLEM16 779133 219 1220-1429 AR104: 96, AR219: 74,AR277: 67, AR283: 59, AR218: 52, AR185: 51, AR089: 49, AR316: 46, AR096:44, AR240: 44, AR313: 42, AR055: 40, AR299: 37, AR282: 37, AR060: 33,AR039: 33, AR300: 24, L0439: 31, L0741: 24, H0056: 13, L0748: 12, H0052:9, H0521: 9, L0776: 8, L0744: 8, L0438: 7, L0754: 7, S0474: 6, L0766: 6,L0742: 6, L0731: 6, L0750: 5, S0278: 4, L5566: 4, L0665: 4, H0522: 4,H0556: 3, H0716: 3, H0657: 3, S0358: 3, H0580: 3, H0599: 3, S0049: 3,H0009: 3, H0553: 3, H0641: 3, S0142: 3, L0764: 3, L0659: 3, L0666: 3,S0126: 3, L0751: 3, H0717: 2, H0656: 2, S0029: 2, S0420: 2, S0360: 2,S0007: 2, H0497: 2, H0486: 2, H0618: 2, H0253: 2, H0581: 2, H0046: 2,S0388: 2, T0010: 2, H0039: 2, H0424: 2, L0456: 2, S0036: 2, H0135: 2,H0551: 2, H0623: 2, H0494: 2, S0002: 2, L0770: 2, L0796: 2, L5575: 2,L5565: 2, L0761: 2, L0662: 2, L0650: 2, L0383: 2, L0663: 2, H0682: 2,L0758: 2, S0434: 2, L0596: 2, L0581: 2, S0242: 2, S0114: 1, H0583: 1,L0422: 1, S0116: 1, H0662: 1, H0305: 1, S0418: 1, L0005: 1, S0444: 1,S0046: 1, S0476: 1, H0645: 1, H0437: 1, H0261: 1, H0392: 1, H0600: 1,H0586: 1, H0574: 1, L0623: 1, H0013: 1, H0250: 1, H0427: 1, H0002: 1,H0575: 1, T0082: 1, H0590: 1, S0010: 1, H0390: 1, T0048: 1, H0318: 1,H0421: 1, H0251: 1, H0232: 1, H0546: 1, H0150: 1, H0041: 1, H0178: 1,H0569: 1, H0620: 1, H0051: 1, S0051: 1, H0510: 1, H0416: 1, H0188: 1,S0312: 1, S0314: 1, H0622: 1, H0213: 1, H0031: 1, L0143: 1, H0032: 1,L0455: 1, S0366: 1, H0038: 1, H0087: 1, H0264: 1, H0268: 1, H0022: 1,H0560: 1, H0625: 1, H0561: 1, S0438: 1, H0509: 1, H0633: 1, H0649: 1,S0144: 1, S0208: 1, H0529: 1, L0769: 1, L0637: 1, L0667: 1, L5568: 1,L0774: 1, L0375: 1, L0805: 1, L0653: 1, L0654: 1, L0661: 1, L0807: 1,L0527: 1, L0382: 1, L0809: 1, L0793: 1, S0006: 1, S0428: 1, S0053: 1,S0310: 1, L0352: 1, H0547: 1, H0684: 1, H0670: 1, H0660: 1, S0152: 1,H0696: 1, S0406: 1, H0555: 1, H0436: 1, S3014: 1, L0743: 1, L0745: 1,L0747: 1, L0749: 1, L0756: 1, L0753: 1, L0755: 1, H0445: 1, S0436: 1,L0485: 1, H0667: 1, H0216: 1, H0543: 1, H0422: 1 and H0008: 1. 210HTLFA13 535937 220 209-304 AR313: 11, AR089: 10, AR039: 9, AR096: 8,AR299: 8, AR282: 7, AR277: 7, AR283: 7, AR104: 7, AR219: 7, AR060: 7,AR270: 7, AR316: 6, AR218: 6, AR310: 6, AR300: 6, AR183: 5, AR233: 5,AR294: 5, AR185: 5, AR237: 5, AR226: 5, AR055: 5, AR238: 5, AR231: 4,AR227: 4, AR296: 4, AR251: 4, AR312: 4, AR240: 4, AR033: 4, AR269: 4,AR290: 3, AR285: 3, AR052: 3, AR184: 3, AR295: 3, AR258: 3, AR186: 3,AR292: 3, AR274: 2, AR205: 2, AR179: 2, AR053: 2, AR061: 2, AR206: 2,AR309: 2, AR293: 2, AR266: 2, AR273: 2, AR259: 1, AR194: 1, AR234: 1,AR182: 1, AR232: 1, AR241: 1, AR284: 1, H0253: 2 and S0011: 1. 211HTLGI89 835069 221 1802-1915 AR283: 67, AR277: 61, AR219: 56, AR282: 51,AR104: 48, AR240: 47, AR316: 46, AR218: 45, AR313: 44, AR089: 42, AR096:40, AR185: 37, AR299: 36, AR055: 34, AR300: 32, AR039: 32, AR060: 31,L0758: 16, L0748: 10, H0620: 7, L0731: 6, H0246: 5, S0007: 4, H0253: 4,L0769: 4, L0754: 4, H0052: 3, H0100: 3, L0638: 3, L5575: 3, L0766: 3,L0650: 3, L0774: 3, S0152: 3, S3014: 3, L0439: 3, H0265: 2, H0556: 2,T0002: 2, S6024: 2, H0656: 2, H0341: 2, S0212: 2, S0376: 2, H0619: 2,H0261: 2, S0222: 2, H0318: 2, H0196: 2, H0012: 2, T0010: 2, H0068: 2,H0551: 2, H0413: 2, H0494: 2, L0770: 2, L5565: 2, L3905: 2, L0768: 2,L0776: 2, S3012: 2, L0741: 2, L0749: 2, L0750: 2, L0759: 2, S0434: 2,L0608: 2, L0595: 2, H0352: 2, S0040: 1, L0760: 1, S0116: 1, S0282: 1,H0638: 1, S0418: 1, S0356: 1, S0444: 1, H0730: 1, H0747: 1, S0476: 1,H0393: 1, H0549: 1, H0550: 1, H0592: 1, H0333: 1, H0486: 1, T0114: 1,H0250: 1, H0069: 1, S0280: 1, H0156: 1, H0599: 1, H0575: 1, H0036: 1,H0618: 1, H0597: 1, H0178: 1, N0006: 1, H0563: 1, H0197: 1, H0199: 1,H0051: 1, H0083: 1, H0060: 1, H0188: 1, H0290: 1, H0284: 1, H0428: 1,H0622: 1, L0483: 1, H0124: 1, H0135: 1, H0163: 1, H0040: 1, H0264: 1,H0412: 1, L0564: 1, H0130: 1, H0641: 1, S0144: 1, S0002: 1, L0763: 1,L0761: 1, L0372: 1, L0643: 1, L0764: 1, L0771: 1, L0648: 1, L0767: 1,L0803: 1, L0804: 1, L0375: 1, L0378: 1, L0659: 1, L0544: 1, L0665: 1,H0703: 1, L0352: 1, H0670: 1, S0328: 1, S0330: 1, H0753: 1, H0522: 1,H0134: 1, S0027: 1, L0747: 1, L0756: 1, L0777: 1, L0753: 1, S0260: 1,H0445: 1, S0436: 1, L0597: 1, H0653: 1 and S0194: 1. 212 HTLIF11 843506222 933-1049 H0253: 7, H0618: 4, H0620: 3, L0794: 3, L0769: 2, L0768: 2,L0439: 2, H0327: 1, H0051: 1, S0250: 1, S0036: 1, L0639: 1, L0761: 1,L0635: 1, L0791: 1, L0664: 1, L0438: 1, H0539: 1, L0741: 1, L0747: 1,L0750: 1, L0756: 1 and L0753: 1. 213 HTNBK13 831967 223 534-599 L0779:5, L0731: 4, L0593: 4, H0046: 3, L0776: 3, L0666: 3, H0031: 2, L0772: 2,L0774: 2, L0805: 2, H0670: 2, L0439: 2, L0754: 2, L0777: 2, L0758: 2,L0590: 2, T0002: 1, L0717: 1, H0632: 1, L0622: 1, T0082: 1, H0581: 1,H0263: 1, T0115: 1, H0597: 1, L0471: 1, H0012: 1, H0620: 1, H0163: 1,T0067: 1, L0770: 1, L0637: 1, L0388: 1, L0657: 1, L0382: 1, L0664: 1,S0126: 1, H0660: 1, S0378: 1, H0521: 1, L0747: 1, L0750: 1, L0756: 1,L0752: 1, L0755: 1, L0759: 1, S0031: 1, L0599: 1 and L0603: 1. 214HTOAM11 664508 224  89-193 AR313: 30, AR039: 27, AR185: 18, AR299: 16,AR300: 13, AR277: 13, AR096: 13, AR089: 12, AR218: 11, AR219: 11, AR316:9, AR240: 9, AR104: 8, AR060: 7, AR055: 6, AR282: 6, AR283: 3, S0010: 1and H0264: 1. 215 HTODH83 580884 225 103-201 AR055: 4, AR060: 4, AR283:2, AR039: 2, AR104: 2, AR219: 2, AR299: 2, AR185: 2, AR282: 1, AR089: 1,AR316: 1, AR240: 1, AR096: 1, AR277: 1, H0264: 1, 216 HTPCO75 853645 226 73-195 AR104: 12, AR219: 11, AR089: 9, AR039: 9, AR282: 8, AR218: 8,AR313: 8, AR060: 8, AR300: 8, AR055: 7, AR316: 7, AR277: 7, AR299: 7,AR096: 7, AR185: 6, AR240: 5, AR283: 4, H0039: 5, L0756: 5, S0448: 3,L0805: 3, L0759: 3, H0265: 2, S0354: 2, L0471: 2, H0674: 2, S0422: 2,L0794: 2, L0517: 2, L0666: 2, L0779: 2, L0777: 2, L0758: 2, H0170: 1,H0556: 1, S0342: 1, S0134: 1, H0637: 1, H0599: 1, H0318: 1, H0263: 1,H0596: 1, H0252: 1, H0428: 1, H0673: 1, H0040: 1, H0264: 1, H0268: 1,H0773: 1, H0538: 1, L0764: 1, L0768: 1, L0766: 1, L0804: 1, L0774: 1,L0652: 1, L0527: 1, L0809: 1, L0519: 1, L0791: 1, H0144: 1, H0520: 1,H0519: 1, H0689: 1, H0648: 1, S0028: 1, L0439: 1, L0731: 1, H0444: 1,H0445: 1, S0434: 1, S0026: 1, S0242: 1 and H0543: 1. 217 HTSFJ32 637720227  93-149 AR104: 9, AR039: 7, AR277: 5, AR282: 4, AR313: 4, AR299: 4,AR240: 3, AR089: 3, AR283: 3, AR300: 3, AR096: 3, AR185: 3, AR055: 2,AR316: 2, AR219: 2, AR218: 2, AR060: 2, H0556: 1, S0114: 1, H0087: 1,H0538: 1, H0695: 1 and L0774: 1. 218 HTTCB60 853401 228  84-884 L0794:11, L0809: 11, L0750: 9, L0805: 8, L0791: 7, L0747: 7, L0800: 6, L0758:6, L0759: 6, H0620: 5, L0749: 5, S0358: 4, H0135: 4, L0769: 4, L0659: 4,L0780: 4, H0556: 3, L0471: 3, H0040: 3, L0804: 3, S0360: 2, H0393: 2,H0550: 2, H0592: 2, H0333: 2, S0049: 2, H0124: 2, S0438: 2, L0771: 2,L0662: 2, L0803: 2, L4501: 2, H0547: 2, L3832: 2, L0779: 2, L0755: 2,L0731: 2, S0434: 2, L0603: 2, H0506: 2, H0713: 1, H0717: 1, H0294: 1,H0662: 1, H0729: 1, H0734: 1, S0045: 1, H0607: 1, H0586: 1, H0587: 1,L3816: 1, T0040: 1, L3653: 1, S0280: 1, H0590: 1, S0010: 1, H0581: 1,H0251: 1, H0041: 1, H0565: 1, H0570: 1, H0123: 1, H0081: 1, H0050: 1,H0188: 1, H0039: 1, H0622: 1, H0038: 1, H0063: 1, H0412: 1, H0413: 1,S0440: 1, S0210: 1, S0002: 1, L0763: 1, L0770: 1, L3905: 1, L0761: 1,L0641: 1, L0768: 1, L0766: 1, L0375: 1, L0806: 1, L0776: 1, L0789: 1,L0790: 1, L0666: 1, L0663: 1, L0665: 1, L2258: 1, L2654: 1, H0520: 1,H0660: 1, H0672: 1, H0539: 1, S0380: 1, H0521: 1, H0696: 1, H0555: 1,L0744: 1, L0748: 1, L0757: 1, H0445: 1, L0584: 1, L0589: 1, S0242: 1,S0194: 1, H0008: 1 and H0352: 1. 219 HTTEE41 840950 229 1171-1197 AR219:84, AR218: 59, AR316: 43, AR313: 32, AR104: 24, AR089: 24, AR185: 24,AR039: 23, AR096: 23, AR299: 21, AR055: 20, AR060: 17, AR282: 14, AR300:14, AR283: 11, AR240: 11, AR277: 10, H0040: 17, H0251: 14, L0758: 10,L0748: 8, L0731: 8, H0494: 7, L0666: 7, H0144: 7, H0659: 7, L0747: 7,L0749: 7, L0757: 7, H0038: 6, H0529: 6, L0770: 6, L0662: 6, L0659: 6,H0013: 5, H0318: 5, H0616: 5, S0440: 5, L0775: 5, L0776: 5, H0519: 5,L0588: 5, L0592: 5, H0341: 4, S0360: 4, H0412: 4, L0663: 4, H0547: 4,L0754: 4, L0595: 4, H0542: 4, H0543: 4, H0423: 4, H0171: 3, H0657: 3,H0656: 3, S0045: 3, L3388: 3, H0581: 3, S0049: 3, T0110: 3, H0046: 3,H0090: 3, H0591: 3, H0551: 3, H0100: 3, H0022: 3, H0625: 3, H0633: 3,S0422: 3, L0375: 3, L0664: 3, H0682: 3, S0406: 3, L0740: 3, H0556: 2,H0241: 2, H0638: 2, S0418: 2, L0005: 2, S0442: 2, S0376: 2, H0722: 2,H0393: 2, L0717: 2, S0222: 2, H0574: 2, H0486: 2, T0040: 2, L0471: 2,S0051: 2, S0003: 2, H0252: 2, L0483: 2, T0006: 2, H0031: 2, H0032: 2,H0124: 2, H0634: 2, H0264: 2, T0042: 2, S0150: 2, H0646: 2, L0763: 2,L0637: 2, L0646: 2, L0374: 2, L0764: 2, L0768: 2, L0653: 2, L0665: 2,H0593: 2, H0435: 2, H0658: 2, H0539: 2, S0152: 2, L3832: 2, H0521: 2,S3014: 2, S0027: 2, S0028: 2, L0439: 2, L0750: 2, L0777: 2, S0436: 2,L0596: 2, L0608: 2, L0604: 2, L0594: 2, L0362: 2, S0026: 2, H0667: 2,S0452: 2, H0506: 2, L0411: 1, H0624: 1, H0170: 1, H0395: 1, H0265: 1,T0002: 1, H0220: 1, H0140: 1, H0159: 1, H0686: 1, H0583: 1, H0650: 1,S0212: 1, H0484: 1, H0664: 1, L0481: 1, S0356: 1, S0354: 1, S0358: 1,S0444: 1, S0408: 1, L3649: 1, H0580: 1, H0747: 1, H0437: 1, H0431: 1,T0104: 1, H0600: 1, H0592: 1, H0586: 1, L3817: 1, H0642: 1, H0632: 1,L2482: 1, T0114: 1, H0244: 1, H0250: 1, H0069: 1, H0156: 1, L0021: 1,H0599: 1, H0036: 1, S0346: 1, H0596: 1, H0544: 1, H0009: 1, N0006: 1,L0157: 1, H0569: 1, H0123: 1, H0242: 1, H0024: 1, H0083: 1, H0375: 1,H0328: 1, H0615: 1, H0428: 1, H0039: 1, H0622: 1, H0213: 1, H0553: 1,L0142: 1, H0628: 1, H0674: 1, H0388: 1, L0456: 1, H0708: 1, H0068: 1,H0598: 1, S0036: 1, H0135: 1, H0087: 1, H0380: 1, H0413: 1, H0056: 1,L0351: 1, T0041: 1, H0334: 1, H0561: 1, H0366: 1, S0448: 1, S0294: 1,H0130: 1, H0641: 1, H0649: 1, S0208: 1, S0002: 1, S0426: 1, L0520: 1,L0631: 1, L0769: 1, L0638: 1, L5565: 1, L0667: 1, L0772: 1, L0372: 1,L0641: 1, L0626: 1, L0794: 1, L0766: 1, L0381: 1, L0650: 1, L0651: 1,L0806: 1, L0655: 1, L0807: 1, L0657: 1, L0636: 1, L0518: 1, L0782: 1,L0382: 1, L0809: 1, L3391: 1, L2263: 1, L2259: 1, L2262: 1, L0565: 1,H0693: 1, L3827: 1, H0520: 1, S0126: 1, H0689: 1, H0670: 1, H0660: 1,H0666: 1, H0648: 1, L0602: 1, H0710: 1, H0518: 1, S0176: 1, H0134: 1,H0555: 1, H0436: 1, H0478: 1, H0631: 1, L0779: 1, L0752: 1, S0434: 1,L0605: 1, L0591: 1, L0599: 1, H0665: 1, S0196: 1, L2368: 1, H0008: 1 andH0352: 1. 220 HTTEZ02 702027 230 250-336 AR299: 21, AR096: 20, AR313:20, AR219: 19, AR218: 19, AR039: 17, AR089: 17, AR316: 17, AR185: 15,AR104: 14, AR277: 14, AR055: 13, AR282: 12, AR240: 12, AR300: 12, AR283:11, AR060: 11, S0474: 15, L0777: 12, L0758: 10, H0038: 9, S0406: 9,L0748: 9, L0595: 9, L0439: 8, H0040: 7, H0521: 7, L0740: 7, L0779: 7,L0747: 6, L0749: 6, L0659: 5, H0599: 4, H0050: 4, H0634: 4, L0770: 4,L0761: 4, L0776: 4, L0663: 4, L0565: 4, H0547: 4, S0436: 4, L0605: 4,H0427: 3, H0673: 3, H0068: 3, L0662: 3, L0766: 3, L0666: 3, H0696: 3,H0436: 3, L0751: 3, H0445: 3, L0596: 3, H0713: 2, H0583: 2, S0442: 2,S0358: 2, H0733: 2, S0046: 2, H0749: 2, S0132: 2, H0619: 2, L0717: 2,H0586: 2, H0013: 2, H0618: 2, H0253: 2, S0010: 2, H0581: 2, H0457: 2,L0471: 2, H0057: 2, H0014: 2, H0039: 2, H0553: 2, H0617: 2, T0041: 2,L0769: 2, L0794: 2, L0649: 2, L0775: 2, L0805: 2, L0655: 2, L0665: 2,S0374: 2, H0520: 2, H0682: 2, H0658: 2, H0710: 2, S0404: 2, L0742: 2,L0755: 2, L0731: 2, L0759: 2, L0591: 2, L0593: 2, H0543: 2, H0624: 1,H0265: 1, H0685: 1, S0342: 1, S0134: 1, S0116: 1, H0341: 1, H0459: 1,S0444: 1, S0360: 1, S0408: 1, H0735: 1, S0045: 1, S0476: 1, S0222: 1,H0392: 1, H0415: 1, H0592: 1, H0486: 1, L3385: 1, T0109: 1, H0635: 1,L0021: 1, H0098: 1, H0575: 1, H0318: 1, H0421: 1, H0596: 1, L0118: 1,H0012: 1, H0373: 1, S6028: 1, H0179: 1, H0719: 1, H0416: 1, H0687: 1,H0252: 1, H0328: 1, H0622: 1, H0032: 1, S0366: 1, S0036: 1, H0090: 1,H0591: 1, H0616: 1, H0412: 1, H0623: 1, H0059: 1, H0641: 1, S0344: 1,L0369: 1, L0763: 1, L0796: 1, L0637: 1, L5566: 1, L0372: 1, L0764: 1,L0364: 1, L0774: 1, L0378: 1, L0379: 1, L0657: 1, L0526: 1, L0664: 1,H0144: 1, H0519: 1, H0593: 1, H0689: 1, H0659: 1, H0672: 1, S0328: 1,S0152: 1, H0522: 1, S0390: 1, S0032: 1, L0750: 1, L0756: 1, L0786: 1,S0031: 1, S0434: 1, L0584: 1, L0608: 1, L0601: 1, S0194: 1, S0196: 1 andS0456: 1. 221 HTWEH94 561680 231  66-311 AR313: 9, AR039: 7, AR096: 5,AR300: 3, AR185: 3, AR089: 3, AR299: 3, AR277: 2, AR316: 2, AR240: 2,AR060: 2, AR104: 2, AR218: 1, AR282: 1, AR055: 1, L0766: 1 and H0436: 1.222 HTXDC77 844258 232  65-520 AR096: 676, AR240: 444, AR039: 281,AR316: 255, AR219: 252, AR218: 219, AR089: 164, AR313: 162, AR299: 150,AR300: 141, AR185: 127, AR282: 113, AR055: 113, AR060: 110, AR283: 94,AR104: 88, AR277: 62, S0344: 14, S0212: 4, S0372: 4, H0555: 4, H0581: 3,S0376: 2, H0597: 2, H0265: 1, S0360: 1, S0222: 1, H0046: 1, H0264: 1,S0370: 1, S0144: 1, S0142: 1, H0521: 1 and S0027: 1. 223 HTXDG92 658730233 216-416 AR218: 44, AR277: 37, AR283: 37, AR219: 35, AR055: 31,AR316: 30, AR089: 29, AR104: 23, AR299: 21, AR240: 20, AR313: 20, AR039:19, AR282: 19, AR185: 19, AR096: 18, AR060: 17, AR300: 17, L0777: 11,H0618: 7, L0438: 6, H0144: 5, L0758: 5, S0410: 4, H0059: 4, L0601: 4,H0556: 3, H0253: 3, H0052: 3, H0620: 3, H0617: 3, L0764: 3, L0768: 3,L0744: 3, L0747: 3, H0265: 2, H0341: 2, S0046: 2, S0222: 2, H0013: 2,H0069: 2, S0049: 2, H0150: 2, H0087: 2, L0351: 2, L0771: 2, L0766: 2,L0665: 2, H0547: 2, H0659: 2, L0748: 2, L0439: 2, L0754: 2, L0749: 2,H0542: 2, L3643: 1, S0040: 1, H0717: 1, H0716: 1, S0114: 1, T0049: 1,H0583: 1, H0657: 1, H0656: 1, H0381: 1, H0663: 1, S0358: 1, H0734: 1,S0007: 1, H0747: 1, S0278: 1, H0261: 1, H0550: 1, H0392: 1, H0486: 1,T0114: 1, S0010: 1, H0581: 1, H0374: 1, H0327: 1, H0545: 1, H0457: 1,H0012: 1, H0024: 1, H0015: 1, H0510: 1, H0594: 1, H0188: 1, H0292: 1,H0286: 1, H0622: 1, H0181: 1, H0135: 1, H0040: 1, H0063: 1, H0100: 1,T0041: 1, H0561: 1, S0440: 1, H0509: 1, H0529: 1, L0640: 1, L0770: 1,L0769: 1, L3905: 1, L5566: 1, L0773: 1, L0662: 1, L0363: 1, L0774: 1,L0775: 1, L0806: 1, L0559: 1, L0783: 1, L0383: 1, L5623: 1, H0698: 1,S0374: 1, H0520: 1, H0519: 1, S0292: 1, S0126: 1, H0682: 1, S0380: 1,H0696: 1, S0027: 1, L0740: 1, L0731: 1, H0445: 1, L0605: 1, L0592: 1 andH0543: 1. 224 HTXET11 581521 234 178-267 AR240: 7, AR055: 6, AR060: 5,AR283: 5, AR282: 5, AR300: 4, AR218: 4, AR277: 4, AR089: 3, AR185: 3,AR104: 3, AR039: 3, AR096: 3, AR316: 3, AR313: 2, AR299: 2, AR219: 2,H0265: 1 and S0442: 1. 225 HTXFA72 853410 235 192-281 AR313: 47, AR039:45, AR299: 26, AR089: 23, AR096: 23, AR185: 22, AR300: 20, AR277: 19,AR219: 17, AR316: 16, AR240: 14, AR104: 14, AR060: 12, AR218: 11, AR282:10, AR055: 8, AR283: 5, H0265: 1 226 HTXJY08 637774 236 108-158 AR055:2, AR060: 2, AR300: 2, AR299: 2, AR313: 2, AR185: 1, AR282: 1, AR089: 1,AR039: 1, AR316: 1, AR219: 1, H0556: 1, S0442: 1, H0036: 1, H0590: 1,H0024: 1, H0100: 1, L0769: 1, L0667: 1, L0438: 1, L0740: 1 and L0777: 1.227 HTXMZ07 834881 237 319-432 AR277: 20, AR104: 8, AR060: 7, AR055: 7,AR316: 6, AR283: 6, AR240: 6, AR300: 5, AR299: 5, AR096: 5, AR282: 5,AR218: 5, AR185: 4, AR039: 4, AR313: 3, AR089: 3, AR219: 3, L0439: 6,H0556: 3, S0007: 2, H0253: 2, L0744: 2, L0740: 2, L0731: 2, H0583: 1,H0656: 1, S0442: 1, H0069: 1, L0021: 1, H0618: 1, H0581: 1, H0041: 1,H0488: 1, L0770: 1, L0800: 1, L0766: 1, L0803: 1, L0375: 1, L0807: 1,L0382: 1, L0791: 1, L0793: 1, L0352: 1, S0432: 1, L0741: 1 and L0779: 1.228 HUKBT67 844446 238 273-392 AR089: 13, AR104: 13, AR055: 12, AR313:12, AR282: 12, AR240: 11, AR299: 11, AR283: 10, AR096: 10, AR060: 9,AR316: 9, AR185: 9, AR039: 9, AR300: 8, AR277: 8, AR218: 8, AR219: 7,S0360: 8, L0748: 8, L0659: 6, L0665: 6, L0759: 6, L0789: 5, L0743: 5,S0346: 4, L0662: 4, L0805: 4, L0752: 4, H0749: 3, L0717: 3, H0644: 3,L0761: 3, L0776: 3, S0028: 3, L0744: 3, L0754: 3, L0749: 3, L0757: 3,S0010: 2, H0059: 2, L3905: 2, L0771: 2, L0804: 2, L0774: 2, L0806: 2,L0809: 2, L0664: 2, L0747: 2, L0758: 2, H0656: 1, S0001: 1, H0734: 1,H0619: 1, L3388: 1, H0392: 1, H0592: 1, H0574: 1, T0082: 1, H0581: 1,H0052: 1, H0544: 1, H0009: 1, H0081: 1, H0620: 1, H0286: 1, H0591: 1,H0038: 1, T0004: 1, H0386: 1, S0144: 1, S0344: 1, L0763: 1, L0667: 1,L0764: 1, L0773: 1, L0794: 1, L0766: 1, L0803: 1, L0650: 1, L0657: 1,L5622: 1, L0793: 1, L0666: 1, H0144: 1, L0352: 1, H0660: 1, H0672: 1,S0328: 1, H0696: 1, S0404: 1, S0406: 1, L0742: 1, L0750: 1, L0779: 1,L0731: 1, S0031: 1, L0596: 1 and L0604: 1. 229 HUKDF20 566823 239214-315 AR055: 7, AR218: 6, AR060: 6, AR300: 5, AR282: 4, AR104: 4,AR313: 4, AR283: 4, AR185: 4, AR299: 4, AR277: 3, AR219: 3, AR089: 3,AR316: 3, AR039: 3, AR240: 3, AR096: 2, H0261: 1, H0266: 1 and H0059: 1.230 HUSCJ14 894699 240  74-661 AR239: 10, AR228: 10, AR227: 9, AR237: 9,AR230: 8, AR233: 8, AR287: 8, AR203: 7, AR288: 7, AR176: 6, AR184: 6,AR199: 6, AR229: 6, AR215: 6, AR190: 6, AR200: 5, AR245: 5, AR174: 5,AR234: 5, AR191: 5, AR180: 4, AR297: 4, AR232: 4, AR226: 4, AR289: 4,AR298: 4, AR194: 4, AR170: 4, AR257: 4, AR061: 3, AR292: 3, AR173: 3,AR231: 3, AR262: 3, AR242: 3, AR284: 3, AR286: 3, AR251: 3, AR179: 3,AR236: 3, AR238: 3, AR255: 3, AR161: 3, AR189: 3, AR162: 3, AR235: 3,AR293: 3, AR282: 3, AR188: 3, AR294: 3, AR165: 3, AR163: 3, AR164: 3,AR166: 3, AR285: 2, AR201: 2, AR181: 2, AR295: 2, AR177: 2, AR247: 2,AR290: 2, AR205: 2, AR300: 2, AR225: 2, AR260: 2, AR198: 2, AR261: 2,AR193: 2, AR291: 2, AR268: 2, AR175: 2, AR270: 2, AR183: 2, AR211: 2,AR296: 2, AR196: 2, AR185: 2, AR258: 2, AR250: 2, AR240: 2, AR178: 2,AR204: 2, AR195: 2, AR060: 2, AR312: 1, AR311: 1, AR210: 1, AR224: 1,AR243: 1, AR299: 1, AR269: 1, AR316: 1, AR275: 1, AR186: 1, AR172: 1,AR039: 1, AR267: 1, AR256: 1, AR263: 1, AR055: 1, AR089: 1, AR217: 1,L2654: 6, L0741: 4, S0192: 4, H0677: 4, H0556: 3, H0013: 3, H0052: 3,L0766: 3, L0744: 3, L0439: 3, L0757: 3, H0265: 2, S0040: 2, S0410: 2,H0599: 2, H0545: 2, H0266: 2, H0030: 2, H0135: 2, L3905: 2, L5622: 2,H0520: 2, H0547: 2, H0519: 2, L0748: 2, L0756: 2, L0777: 2, L0780: 2,L0758: 2, L0485: 2, L0604: 2, H0739: 1, H0713: 1, S0134: 1, S0218: 1,H0656: 1, L2909: 1, S0212: 1, H0663: 1, S0420: 1, L1562: 1, S0360: 1,S0408: 1, H0742: 1, S0132: 1, S0476: 1, H0393: 1, H0587: 1, T0040: 1,H0575: 1, H0309: 1, H0009: 1, L0471: 1, H0620: 1, H0510: 1, H0290: 1,S0250: 1, S0022: 1, T0023: 1, H0488: 1, H0268: 1, T0041: 1, T0042: 1,H0538: 1, S0210: 1, L0763: 1, L0800: 1, L0771: 1, L0794: 1, L0804: 1,L0774: 1, L0775: 1, L5623: 1, L0793: 1, L2652: 1, L2257: 1, L2260: 1,L0710: 1, L2262: 1, H0144: 1, H0593: 1, H0435: 1, H0521: 1, H0555: 1,L0743: 1, L0754: 1, L0779: 1, L0752: 1, S0031: 1, S0436: 1, L0596: 1,L0605: 1, L0601: 1, S0106: 1, H0667: 1, S0276: 1 and L3576: 1. 231HUSGL67 792637 241 350-493 AR252: 82, AR250: 77, AR253: 70, AR222: 49,AR219: 44, AR218: 40, AR254: 37, AR169: 32, AR171: 31, AR168: 30, AR214:28, AR217: 27, AR221: 25, AR215: 22, AR309: 22, AR096: 21, AR316: 20,AR170: 20, AR216: 19, AR172: 18, AR223: 18, AR264: 17, AR224: 16, AR308:16, AR312: 15, AR263: 15, AR183: 14, AR268: 13, AR313: 13, AR039: 13,AR225: 12, AR311: 11, AR180: 10, AR291: 10, AR271: 10, AR181: 9, AR269:9, AR240: 9, AR177: 9, AR176: 9, AR242: 8, AR299: 8, AR229: 8, AR213: 8,AR173: 8, AR290: 8, AR235: 8, AR247: 8, AR179: 8, AR243: 7, AR270: 7,AR266: 7, AR182: 7, AR238: 7, AR178: 7, AR245: 7, AR189: 7, AR053: 7,AR246: 6, AR267: 6, AR272: 6, AR190: 6, AR089: 6, AR165: 6, AR175: 6,AR193: 6, AR275: 6, AR164: 6, AR162: 6, AR166: 6, AR261: 6, AR212: 6,AR161: 6, AR163: 5, AR289: 5, AR300: 5, AR174: 5, AR211: 5, AR199: 5,AR234: 5, AR197: 5, AR297: 5, AR200: 5, AR210: 5, AR296: 5, AR282: 5,AR295: 5, AR237: 5, AR198: 5, AR283: 4, AR204: 4, AR287: 4, AR231: 4,AR191: 4, AR288: 4, AR285: 4, AR230: 4, AR257: 4, AR274: 4, AR055: 4,AR033: 4, AR195: 4, AR061: 4, AR188: 4, AR196: 4, AR236: 4, AR293: 4,AR294: 3, AR185: 3, AR104: 3, AR239: 3, AR286: 3, AR226: 3, AR203: 3,AR277: 3, AR060: 3, AR205: 3, AR262: 3, AR255: 3, AR228: 3, AR201: 3,AR256: 3, AR260: 2, AR233: 2, AR258: 2, AR232: 2, AR227: 2, AR192: 1,S0358: 2, S0116: 1, S0360: 1, S0045: 1, H0497: 1, H0486: 1, H0250: 1,S0010: 1, S0474: 1, H0266: 1, H0271: 1, T0006: 1, H0412: 1, L3815: 1,L0766: 1, L2258: 1, H0710: 1, H0518: 1, S3014: 1 and H0543: 1. 232HUSGU40 684975 242 500-640 AR218: 67, AR219: 57, AR096: 53, AR240: 49,AR283: 44, AR313: 43, AR316: 37, AR089: 33, AR039: 32, AR185: 29, AR277:25, AR282: 24, AR104: 24, AR060: 23, AR299: 23, AR300: 22, AR055: 19 233HUSIR18 762858 243  83-151 L0748: 4, H0622: 3, L0777: 3, H0624: 2,H0013: 2, H0520: 2, H0539: 2, L0439: 2, L0754: 2, L0747: 2, L0757: 2,L0758: 2, L0593: 2, L0002: 1, H0664: 1, H0580: 1, S0007: 1, H0497: 1,H0333: 1, H0599: 1, H0581: 1, L0483: 1, H0598: 1, H0040: 1, H0412: 1,L0351: 1, T0041: 1, L0769: 1, L0771: 1, L0662: 1, L0767: 1, L0768: 1,L0766: 1, L0381: 1, L0806: 1, L0656: 1, L0659: 1, L0809: 1, L0663: 1,L0665: 1, H0672: 1, S0152: 1, L0740: 1, L0749: 1, L0750: 1, L0779: 1,L0752: 1, L0480: 1, L0591: 1 and H0543: 1. 234 HUVDJ48 564853 244196-213 AR055: 6, AR060: 5, AR283: 5, AR039: 5, AR185: 4, AR096: 4,AR240: 4, AR104: 4, AR299: 4, AR300: 3, AR089: 3, AR316: 3, AR313: 3,AR282: 3, AR218: 2, AR277: 2, AR219: 2, H0393: 1, H0056: 1 and L0662: 1.235 HWDAC26 821335 245 242-349 AR096: 144, AR218: 136, AR219: 123,AR316: 112, AR240: 70, AR089: 66, AR104: 55, AR313: 49, AR060: 49,AR185: 48, AR299: 46, AR039: 41, AR055: 35, AR283: 22, AR282: 22, AR277:21, AR300: 19, AR198: 5, AR184: 5, AR183: 5, AR194: 4, AR284: 4, AR270:4, AR229: 4, AR269: 3, AR292: 3, AR310: 3, AR182: 3, AR265: 3, AR175: 3,AR238: 3, AR293: 3, AR268: 2, AR294: 2, AR291: 2, AR213: 2, AR192: 2,AR286: 2, AR312: 2, AR234: 2, AR226: 2, AR296: 2, AR249: 2, AR1586: 2,AR177: 2, AR053: 2, AR290: 2, AR285: 2, AR227: 2, AR258: 2, AR052: 2,AR266: 2, AR205: 1, AR237: 1, AR298: 1, AR179: 1, AR274: 1, AR241: 1,AR289: 1, AR233: 1, AR247: 1, AR295: 1, AR256: 1, AR280: 1, AR259: 1,AR231: 1, H0580: 1, S0300: 1, H0600: 1, L0783: 1, L0438: 1, L0439: 1 andL0758: 1. 236 HWDAJ01 794016 246 288-362 AR282: 2, AR060: 2, AR055: 2,AR185: 2, AR283: 1, AR104: 1, AR316: 1, AR039: 1, AR218: 1, H0600: 1 237HBDAB91 864374 247 671-760 AR282: 3, AR219: 1, H0551: 2, L0803: 2,L0439: 2, L0750: 2, S0308: 2, L0644: 1, L0655: 1, L0809: 1, L0780: 1 andL0752: 1. 238 HILCA24 869856 248  191-1174 AR316: 4, AR282: 2, AR096: 1,AR299: 1, AR039: 1, L0748: 4, H0090: 2, L0659: 2, H0521: 2, L0777: 2,L0608: 2, H0543: 2, T0002: 1, S0114: 1, L3658: 1, S0358: 1, S0408: 1,L3649: 1, T0109: 1, H0581: 1, H0622: 1, H0031: 1, H0644: 1, S0002: 1,L0657: 1, L0526: 1, L0789: 1, L0664: 1, S0380: 1, H0522: 1, L0749: 1 andL0779: 1. 239 HYABC84 865064 249 1080-1268 AR313: 19, AR219: 16, AR218:13, AR104: 13, AR096: 11, AR316: 11, AR240: 10, AR299: 10, AR089: 10,AR282: 9, AR185: 9, AR039: 9, AR283: 8, AR277: 7, AR060: 6, AR055: 5,AR300: 5 240 HE2CA60 888705 250 1731-1754 AR313: 86, AR299: 44, AR277:42, AR283: 37, AR039: 37, AR316: 36, AR218: 34, AR096: 34, AR219: 34,AR089: 32, AR185: 32, AR104: 30, AR282: 23, AR300: 23, AR055: 22, AR060:16, AR240: 16, H0305: 16, L0777: 11, L0471: 10, S0422: 9, L0766: 9,H0624: 8, H0013: 7, H0170: 6, L2551: 6, H0046: 6, L0665: 6, L0598: 5,L0662: 5, L0776: 5, H0547: 5, L0758: 5, L0589: 5, H0171: 4, L0659: 4,L0666: 4, L0663: 4, L0756: 4, L0731: 4, S0358: 3, L2744: 3, L3655: 3,H0581: 3, H0457: 3, S0406: 3, L0744: 3, L0439: 3, L0752: 3, S0436: 3,H0542: 3, H0543: 3, L3643: 2, H0650: 2, H0657: 2, S0116: 2, S0442: 2,S0354: 2, L0717: 2, S0414: 2, H0486: 2, T0040: 2, H0318: 2, H0421: 2,H0428: 2, H0553: 2, H0090: 2, H0040: 2, H0063: 2, H0641: 2, L0769: 2,L0761: 2, L0764: 2, L0650: 2, L0774: 2, L0805: 2, L0657: 2, H0144: 2,L3811: 2, L3832: 2, H0521: 2, S0404: 2, L0741: 2, L0740: 2, L0747: 2,L0759: 2, S0434: 2, L0362: 2, H0685: 1, S0218: 1, L0785: 1, H0341: 1,H0255: 1, H0663: 1, H0662: 1, H0402: 1, S0376: 1, S0360: 1, S0410: 1,L3645: 1, L3646: 1, H0637: 1, H0741: 1, H0722: 1, H0735: 1, S0046: 1,H0749: 1, S0300: 1, L2758: 1, L2767: 1, L3388: 1, S0222: 1, H0592: 1,H0586: 1, H0587: 1, H0559: 1, L3653: 1, H0427: 1, L0021: 1, H0037: 1,H0746: 1, H0263: 1, H0544: 1, H0050: 1, H0057: 1, L0163: 1, H0051: 1,S0022: 1, H0328: 1, T0023: 1, H0673: 1, H0674: 1, H0591: 1, H0038: 1,H0551: 1, T0067: 1, H0100: 1, L0065: 1, S0440: 1, H0649: 1, H0529: 1,L0369: 1, L0763: 1, L0667: 1, L0630: 1, L0372: 1, L0521: 1, L0533: 1,L0775: 1, L0651: 1, L0806: 1, L0655: 1, L0661: 1, L0807: 1, L0656: 1,L0809: 1, L3872: 1, L0790: 1, L0664: 1, L2655: 1, L3663: 1, S0374: 1,L2706: 1, H0520: 1, H0435: 1, H0660: 1, H0672: 1, S0328: 1, H0539: 1,S0380: 1, H0753: 1, S0004: 1, H0696: 1, L0748: 1, L0754: 1, L0750: 1,L0753: 1, S0031: 1, H0444: 1, L0588: 1, L0605: 1, L0485: 1, H0216: 1,S0242: 1, H0423: 1, S0458: 1 and H0721: 1. 241 HPQAX38 845752 251295-345 AR313: 99, AR039: 86, AR300: 47, AR299: 43, AR096: 43, AR185:41, AR089: 37, AR277: 36, AR104: 30, AR240: 30, AR219: 29, AR316: 28,AR218: 23, AR282: 20, AR060: 19, AR055: 12, AR283: 6, S0136: 462 andH0413: 1. 242 HE8FD92 901142 252 2141-2272 AR055: 6, AR299: 6, AR060: 6,AR240: 5, AR218: 5, AR219: 5, AR300: 5, AR185: 5, AR089: 4, AR316: 3,AR096: 3, AR104: 3, AR039: 3, AR277: 3, AR283: 2, AR282: 2, AR313: 2

Table 1C summarizes additional polynucleotides encompassed by theinvention (including cDNA clones related to the sequences (Clone ID:),contig sequences (contig identifier (Contig ID:) contig nucleotidesequence identifiers (SEQ ID NO:X)), and genomic sequences (SEQ IDNO:B). The first column provides a unique clone identifier, “Clone ID:”,for a cDNA clone related to each contig sequence. The second columnprovides the sequence identifier, “SEQ ID NO:X”, for each contigsequence. The third column provides a unique contig identifier, “ContigID:” for each contig sequence. The fourth column, provides a BACidentifier “BAC ID NO:A” for the BAC clone referenced in thecorresponding row of the table. The fifth column provides the nucleotidesequence identifier, “SEQ ID NO:B” for a fragment of the BAC cloneidentified in column four of the corresponding row of the table. Thesixth column, “Exon From-To”, provides the location (i.e., nucleotideposition numbers) within the polynucleotide sequence of SEQ ID NO:Bwhich delineate certain polynucleotides of the invention that are alsoexemplary members of polynucleotide sequences that encode polypeptidesof the invention (e.g., polypeptides containing amino acid sequencesencoded by the polynucleotide sequences delineated in column six, andfragments and variants thereof). TABLE 1C SEQ ID EXON cDNA Clone ID SEQID NO: X CONTIG ID: BAC ID: A NO: B From-To H6BSF56 11 762968 AC069362517 1-131 H6BSF56 11 762968 AC027584 518 1-162 H6BSF56 11 762968AC011101 519 1-100 H6BSF56 11 762968 AC073446 520 1-140 H6BSF56 11762968 AC026556 521 1-114 H6BSF56 11 762968 AL136171 522 1-61 H6BSF56 11762968 AC025975 523 1-136 H6BSF56 11 762968 AC073219 524 1-123 H6BSF5611 762968 AL162741 525 1-45 H6BSF56 11 762968 AC027584 526 1-368 H6BSF5611 762968 AC073446 527 1-52 2626-2925 H6BSF56 11 762968 AL162741 5281-102 H6EEC72 13 889401 AC012314 529 1-181 1281-1463 2719-2983 3158-34113804-6347 6745-6879 7118-7319 7420-7521 7859-8305 8552-8602 9988-1033410415-10778 11003-11127 11210-11303 11334-11832 13093-13145 13703-1383713918-14152 15415-15511 15613-15742 15998-16087 16231-16307 16447-1721118520-18796 21777-22001 H6EEC72 13 889401 AC009968 530 1-180 1275-14572712-2976 3150-3403 3796-6332 6730-6864 7103-7303 7404-7505 7843-82898536-8586 9970-10312 10393-10756 10981-11105 11188-11805 13068-1312013678-13812 13905-13994 H6EEC72 13 889401 AC012314 531 1-43 861-10311576-1743 1924-2132 2203-2432 2473-2905 3177-3360 3651-4332 4422-45834830-4995 5086-5365 H6EEC72 13 889401 AC009968 532 1-43 857-10271570-1737 1918-2126 2197-2426 2467-2899 3171-3354 3644-4326 4416-45774824-4989 5080-5360 H6EEU40 14 757048 AC026285 533 1-414 440-1918H6EEU40 14 757048 AC023920 534 1-416 442-1920 H6EEU40 14 757048 AC026285535 1-1458 1729-1836 H6EEU40 14 757048 AC023920 536 1-1459 1730-1837HACAB68 15 584773 AL160283 537 1-2811 HACAB68 15 584773 AL354793 5381-3734 3843-4723 HACAB68 15 584773 AL356058 539 1-3055 3165-4045 HACBJ5616 847112 AC069497 540 1-117 2470-3367 4908-5262 5641-5756 7886-82009815-11138 HACBJ56 16 847112 AC007104 541 1-802 2342-2695 3074-31895319-5633 7248-8571 HACBJ56 16 847112 AC069497 542 1-453 HACBJ56 16847112 AC007104 543 1-453 HADMB15 17 847116 AC026666 544 1-385 406-780HADMB15 17 847116 AC026281 545 1-114 430-875 896-1262 HAGFS57 18 847120AC021238 546 1-140 3343-3636 5052-5179 5712-5796 6486-6918 7867-84048934-9513 9711-10538 10984-11992 12080-12349 12485-12857 13895-1421214994-15054 15169-15297 16132-16211 17721-17811 18135-18354 18363-1844419661-19720 19841-20784 20920-21236 22168-24079 HAGFS57 18 847120AC066613 547 1-433 1382-1919 2449-3028 3226-4053 4499-5507 5595-58646000-6372 7410-7727 8509-8569 8684-8812 9647-9726 11236-1132611650-11869 11878-11959 13176-13235 13356-14299 14435-14752 15684-17595HAJAY92 21 845601 AL353726 548 1-2332 HAJAY92 21 845601 AL353726 5491-115 HAJAY92 21 845601 AL353726 550 1-115 HATCD80 23 826098 AL158801551 1-1974 HATCD80 23 826098 AL158801 552 1-90 HATEH20 24 836056AC006207 553 1-2845 HATEH20 24 836056 AC006207 554 1-76 1150-12901699-2395 HBAGD86 25 838799 AC016755 555 1-41 1648-1993 2035-35523554-6713 HBAGD86 25 838799 AC016755 556 1-161 696-809 2256-27536910-6991 7733-7857 9267-9458 10650-10734 11114-11562 11678-1180112524-12817 14494-15914 HBAGD86 25 838799 AC016755 557 1-217 HBGNC72 27892131 AC016588 558 1-67 319-423 3335-3462 3594-3680 4721-5143 5551-6677HBHAA05 28 603174 AL353743 559 1-677 HBHAA05 28 603174 AL161453 5601-677 HBHAA05 28 603174 AL161453 561 1-339 HBHAA81 29 846465 AC006059562 1-230 1619-1699 1953-2090 2986-3054 3665-3786 3902-4406 4457-46745129-5531 5660-5811 5934-5969 7563-7959 8086-9195 9591-9735 9788-10149HBHAA81 29 846465 AC018471 563 1-230 1619-1699 1965-2090 2986-30543665-3786 3902-4405 4456-4673 5128-5530 5659-5810 5933-5968 7561-79578084-9193 9589-9733 9786-10146 HBHAA81 29 846465 AC006059 564 1-340501-802 HBHAA81 29 846465 AC006059 565 1-661 1538-1684 3489-36803832-3933 4241-4410 5782-5872 5998-6150 HBHAA81 29 846465 AC018471 5661-661 1539-1672 HBHAA81 29 846465 AC018471 567 1-340 501-802 HBJAB02 31837309 AC015651 568 1-35 159-252 410-783 786-830 953-1035 1452-15531651-2071 2161-2264 2352-2454 2494-2758 2847-3006 3135-3272 3477-41384907-5738 5972-6059 6132-6367 6650-6834 6915-7010 7091-7658 7662-945710122-10222 11415-11534 12386-12418 13253-13584 13635-13867 14881-1532615851-16013 16529-16816 17430-17529 18140-18269 18634-18734 19189-1936920434-21105 21912-22008 HBJAB02 31 837309 AC015651 569 1-2097 5308-54955696-5742 5890-6249 7370-7525 7850-8236 8359-8463 8597-8770 8919-90289213-9353 9517-9639 9765-9874 9944-11023 11124-11219 11315-1161311708-12241 12431-12666 12744-12802 12976-13087 13374-13914 14728-15500HBJAC40 32 841235 AC007606 570 1-89 520-616 811-972 1604-1874 1982-50385125-5260 6459-6956 7370-7473 7507-7774 8952-9321 HBJAC40 32 841235AC007606 571 1-403 428-1236 HBJDW56 34 520401 AC005532 572 1-626 HBJDW5634 520401 AC005532 573 1-516 HBJDW56 34 520401 AC005532 574 1-176HBMBM96 37 561935 AP000786 575 1-1121 HBMBM96 37 561935 AP000786 5761-192 HBMTM11 38 589515 AC005412 577 1-5153 HBMTM11 38 589515 AC068025578 1-5153 HBMTM11 38 589515 AC005412 579 1-401 2025-2517 3932-40324495-4619 5190-5319 6731-7210 7410-7747 7885-7989 10428-1052812252-12623 14008-14169 15102-15535 15963-16112 17178-17644 20468-2112621810-25012 HBMTM11 38 589515 AC005412 580 1-134 HBMTM11 38 589515AC068025 581 1-134 HBMTM11 38 589515 AC068025 582 1-3201 HBSAK32 41856387 AL161656 583 1-325 363-460 507-980 1258-1440 1691-2081 2107-23472442-2595 2622-3125 3993-4605 4876-5153 5309-5877 HBSAK32 41 856387AL161656 584 1-186 511-636 HCDCY76 43 837972 AP001528 585 1-3072 HCDCY7643 837972 AP001528 586 1-380 HCE1G78 45 761204 AC005005 587 1-1481171-1291 1870-3004 3641-3752 3952-4068 4387-4561 4980-5091 5243-53495497-5683 5962-6073 6855-7088 9649-9785 10127-10269 10438-1050610631-10739 10938-11726 HCE1G78 45 761204 AC005005 588 1-432 HCE5F78 46838101 AC007318 589 1-1782 HCE5F78 46 838101 AC007318 590 1-98 HCEEU1849 688041 AC008469 591 1-169 HCEEU18 49 688041 AC026400 592 1-170HCEEU18 49 688041 AC008469 593 1-304 420-602 1427-2108 2323-26453613-3987 4129-4442 4600-4731 4868-5039 5408-5538 5624-5776 6317-7734HCEEU18 49 688041 AC008469 594 1-294 HCEEU18 49 688041 AC026400 595 1-98HCEEU18 49 688041 AC026400 596 1-407 HCEGG08 50 844506 AC078898 5971-640 HCEGG08 50 844506 AC074196 598 1-606 HCEGG08 50 844506 AC077693599 1-628 HCEGG08 50 844506 AC027037 600 1-640 HCEGG08 50 844506AC026757 601 1-513 HCEGG08 50 844506 AC027036 602 1-612 HCEGG08 50844506 AC074108 603 1-462 HCEGG08 50 844506 AC074226 604 1-640 HCEGG0850 844506 AG073166 605 1-640 HCEGG08 50 844506 AC068667 606 1-654HCEGG08 50 844506 AC024594 607 1-414 HCEGG08 50 844506 AC024261 6081-647 HCEGG08 50 844506 AC078893 609 1-640 HCEGG08 50 844506 AC073555610 1-640 HCEGG08 50 844506 AG069474 611 1-571 HCEGG08 50 844506AC068924 612 1-640 HCEGG08 50 844506 AC066689 613 1-639 HCEGG0S 50844506 AC035249 614 1-397 HCEGG08 50 844506 AC034258 615 1-648 HCEGG0850 844506 AC027135 616 1-434 HCEGG08 50 844506 AC027035 617 1-624HCEGG08 50 844506 AC027034 618 1-509 HCEGG08 50 844506 AC026815 6191-654 HCEGG08 50 844506 AC025781 620 1-546 HCEGG08 50 844506 AC078894621 1-654 HCFLN88 51 610000 AC005089 622 1-594 1779-2065 2224-24113295-3588 3962-4463 5317-5561 5835-6210 6750-7793 HCFLN88 51 610000AC005089 623 1-141 HCFLN88 51 610000 AC005089 624 1-215 HCMSX51 53788643 U96629 625 1-3014 HCMSX51 53 788643 AC040975 626 1-3014 HCNCO1154 775086 AC011319 627 1-700 HCNCO11 54 775086 AC069204 628 1-700HCNCO11 54 775086 AC011319 629 1-354 HCNCO11 54 775086 AC011319 6301-338 HCNCO11 54 775086 AC069204 631 1-354 HCQBH72 56 637548 AC073530632 1-1790 HCQBH72 56 637548 AC073530 633 1-106 HCQBH72 56 637548AC073530 634 1-410 HCUCF89 58 637986 AC022554 635 1-1066 HCUCF89 58637986 AC022554 636 1-692 HCUCF89 58 637986 AC022554 637 1-643 HCUCK4459 790277 AC007842 638 1-1118 HCUCK44 59 790277 AC007842 639 1-415HCUCK44 59 790277 AC007842 640 1-101 HCWAE64 61 535893 AL157935 6411-1319 2024-2316 2937-2984 3126-3281 5595-5703 5788-6574 6667-67336788-6880 6962-7303 8111-11869 12019-12418 12420-12679 13140-13191HCWAE64 61 535893 AL157935 642 1-1316 HCWAE64 61 535893 AL157935 6431-309 HDPDI72 62 897277 AL139238 644 1-76 3170-3542 4724-5613 6598-67196954-7373 8256-8349 10408-11003 HDPDI72 62 897277 AL139238 645 1-279HDPIY31 65 886159 AL356790 646 1-114 949-1189 2041-2318 2541-27112797-2871 3152-7720 HDPIY31 65 886159 AL118506 647 1-241 1067-13171567-1737 1823-1897 2178-6746 HDPIY31 65 886159 AL356790 648 1-104116-297 HDPIY31 65 886159 AL356790 649 1-481 HDPIY31 65 886159 AL118506650 1-89 HDPOO76 68 838594 AC006483 651 1-109 132-434 604-3482 HDPOO7668 838594 AC026717 652 1-1820 HDPOO76 68 838594 AC035147 653 1-1820HDPOO76 68 838594 AC026692 654 1-1823 HDPOO76 68 838594 AC073481 6551-2558 HDPOO76 68 838594 AC006483 656 1-216 HDPOO76 68 838594 AC006483657 1-231 HDPOO76 68 838594 AC073481 658 1-231 HDPPQ30 69 684292AL022315 659 1-968 HDPPQ30 69 684292 AL022315 660 1-255 HE2CM39 71553651 AC018391 661 1-3570 3779-3904 4646-5979 6339-6701 6710-8473HE2CM39 71 553651 AC018391 662 1-438 HE2CM39 71 553651 AC018391 6631-1402 1586-1871 2685-2797 3088-3503 4900-5170 5789-5882 6089-6195HE2PO93 72 771655 AC020894 664 1-353 749-1198 2724-2986 4932-55787481-7617 8108-8257 8515-8849 9840-9968 10287-10827 11376-1447414652-15073 15510-17083 17304-20501 HE2PO93 72 771655 AC008590 665 1-6482551-2687 3178-3327 3585-3919 4910-5038 5357-5897 6446-10147 10584-1215912380-15574 HE2PO93 72 771655 AC021468 666 1-353 749-1198 2724-29864934-5579 7482-7618 8109-8258 8516-8850 9841-9969 10288-1082811377-13627 13631-13748 13762-15078 15515-17088 17309-20507 HE2PO93 72771655 AC020894 667 1-372 HE2PO93 72 771655 AC020894 668 1-315 893-1242HE2PO93 72 771655 AC021468 669 1-350 HB2PO93 72 771655 AC021468 6701-372 HE6FU11 73 827236 AL021578 671 1-116 2674-2776 3489-4063 7279-74029706-10120 10217-10368 12042-12219 12315-12924 14271-14380 14463-1484216153-16301 HE6FV29 74 588454 AL162401 672 1-1425 HEBDF77 77 692347AL078460 673 1-1933 HEBDF77 77 692347 AL078460 674 1-269 HEBDF77 77692347 AL078460 675 1-176 HEBDQ91 78 840288 AC008623 676 1-2883 HBBDQ9178 840288 AC008623 677 1-350 HEBDQ91 78 840288 AC008623 678 1-555HEBFR46 79 847064 AC006483 679 1-70 282-644 789-4243 HEBFR46 79 847064AC073481 680 1-2167 2174-3461 HEBFR46 79 847064 AC006483 681 1-344HEBFR46 79 847064 AC006483 682 1-195 HEBGE07 80 798096 AC021918 6831-1899 HEBGE07 80 798096 AC021918 684 1-225 HEGAU15 81 834379 AC009404685 1-1121 HEGAU15 81 834379 AC011638 686 1-1119 HEGAU15 81 834379AC009404 687 1-363 HEGAU15 81 834379 AC009404 688 1-446 HEGAU15 81834379 AC011638 689 1-446 HEGAU15 81 834379 AC011638 690 1-363 HBQBF8982 786205 AL160055 691 1-801 HEQBF89 82 786205 AC009485 692 1-800HEQBF89 82 786205 AL158827 693 1-827 HEQBF89 82 786205 AC009485 6941-100 HEQBF89 82 786205 AL158827 695 1-279 HEQBF89 82 786205 AL158827696 1-138 152-192 HFCEI04 83 692438 AC068996 697 1-865 HFCEI04 83 692438AC068303 698 1-865 HFEAY59 84 658685 AC005919 699 1-490 976-10631264-1351 1663-1956 2076-2238 2674-2837 2910-3034 4517-4686 4804-50215234-5282 5397-5729 7103-7442 HFEAY59 84 658685 AC005919 700 1-155HFIJA68 85 847074 AC010550 701 1-127 HFKEU12 86 634006 AC010443 7021-1026 HFKEU12 86 634006 AC021087 703 1-1026 HFKEU12 86 634006 AC027825704 1-1026 HFKEU12 86 634006 AC027825 705 1-263 HFTDH56 89 862021AC023154 706 1-1503 1728-2093 2281-2361 3191-3738 3787-4515 HFVHW43 90570948 AL132795 707 1-253 1142-1455 1576-2150 2529-2966 4374-44714991-5361 6514-7738 7936-8053 9858-9979 11930-12101 12401-1252512531-12712 16593-16786 17053-17214 18919-19396 21174-21327 21724-2229622515-23071 HFVHW43 90 570948 AL132795 708 1-6181 HPVHW43 90 570948AL132795 709 1-287 622-861 HGBHP91 91 693011 AL356056 710 1-1048 HGBHP9191 693011 AL136982 711 1-1048 HGBHP91 91 693011 AL356056 712 1-238HGBHP91 91 693011 AL356056 713 1-135 HGBHP91 91 693011 AL136982 7141-238 HGBHP91 91 693011 AL136982 715 1-136 HHEAK45 92 765278 AL035690716 1-2148 4277-4419 5252-5365 5452-6322 6863-7710 HHEAK45 92 765278AC010388 717 1-2149 HHEAK45 92 765278 AL035690 718 1-732 HHEAK45 92765278 AL035690 719 1-86 175-566 HHEGS55 93 858372 AC009679 720 1-565HHEGS55 93 858372 AC016824 721 1-902 HHFFS40 96 824059 AC022423 7221-2017 KHFFS40 96 824059 AC025178 723 1-2017 HHFFS40 96 824059 AC022444724 1-2017 HHGDT26 98 658692 AC010754 725 1-1584 HHGDT26 98 658692AC016127 726 1-1584 1639-1876 HHGDT26 98 658692 AC023989 727 1-15841639-1876 HHPFU28 99 824573 AC069200 728 1-2595 HHPFU28 99 824573AC069200 729 1-3998 HHPFU28 99 824573 AC069200 730 1-777 HHSBI06 100639097 AF285442 731 1-1170 1250-1439 1565-1850 2214-2632 HHSBI06 100639097 AF271897 732 1-1174 1253-1444 1568-1853 2217-2659 4394-48765269-6156 7228-8366 8574-8852 HHSBI06 100 639097 AC025857 733 1-11721254-1442 1566-1851 2215-2618 4423-4905 5298-6179 7253-8391 8599-8877HHSBI06 100 639097 AF285442 734 1-483 HHSBI06 100 639097 AF285442 7351-323 420-676 774-935 1372-1637 HHSBI06 100 639097 AF271897 736 1-522HHSBI06 100 639097 AF271897 737 1-323 420-676 774-935 1372-1637 HHSBI06100 639097 AC025857 738 1-522 HHSBI06 100 639097 AC025857 739 1-323420-676 774-935 1372-1637 HHSBI65 101 801910 AF205589 740 1-17031798-2217 2302-3089 HHSBI65 101 801910 AF205589 741 1-531 571-17591862-2104 2219-2722 HHSDI53 102 862028 AP001456 742 1-1611 1654-20202187-2263 HHSDI53 102 862028 AL109936 743 1-1611 1654-2020 2186-23222673-3243 3291-3857 4276-4892 5002-5380 8185-8499 8705-8842 10146-1029812526-12652 12780-14327 HHSDI53 102 862028 AP001456 744 1-482 HHSDI53102 862028 AL109936 745 1-188 HISAT67 103 843549 AC013403 746 1-753852-1545 1734-1816 1930-2061 2259-2428 2573-2648 2685-2987 3135-41264242-4543 4732-4905 5033-5145 5298-5341 5530-5715 6059-6126 HISAT67 103843549 AC013403 747 1-102 HJMAV41 106 862029 AC008998 748 1-239 975-11191204-1298 3076-3230 4100-4205 5256-5376 5476-5596 6626-6943 7508-8143HJPCH08 109 840365 AC004826 749 1-71 475-867 2289-2390 2475-25963191-3333 3458-3644 3729-3859 4038-4233 4338-4451 4558-4626 4832-49775108-5272 5380-5622 5698-5816 5965-6067 6380-6580 6829-6920 7162-72997943-10018 10503-10623 10699-10776 10917-11336 12343-12406 12731-13275HJPCH08 109 840365 AC004826 750 1-406 862-1119 1423-1689 2886-29895361-5431 5969-6059 6874-7181 9823-9980 10928-11194 12667-1283817063-18165 18168-18649 18785-19579 19733-19780 20247-20355 21063-2141521546-22630 23320-23541 24276-24323 24510-24602 24903-25357 26015-2711527309-28272 28601-28879 29413-29552 30539-30602 30728-31110 31231-3135332257-32325 33895-34173 35081-35392 37763-37860 38789-38822 38920-39119HJPCH08 109 840365 AC004826 751 1-424 2065-2241 HKGBF25 110 738797AL390999 752 1-1996 HKGBF25 110 738797 AC012079 753 1-1997 HKIXC44 111716213 AC016240 754 1-195 476-552 679-763 1040-1119 1998-3764 HKIXC44111 716213 AF261720 755 1-195 475-551 678-762 1039-1118 1998-3764HKIXC44 111 716213 AC016240 756 1-423 HKIXC44 111 716213 AF261720 7571-423 HKIXC44 111 716213 AF261720 758 1-206 HKTAB41 112 695732 AC006451759 1-737 HLDBG17 113 855953 AL161798 760 1-1403 HLHAP05 116 638476AC009097 761 1-101 HLHCS23 117 560663 AL356385 762 1-1419 HLHCS23 117560663 AC016501 763 1-1419 HLHCS23 117 560663 AL356385 764 1-560 HLHCS23117 560663 AC016501 765 1-560 HLICO10 120 658740 AL031685 766 1-1651532-2565 2618-3686 4070-4320 4665-5083 5172-5547 5902-6305 7276-91009742-9863 10008-10531 11381-11716 12759-13260 15686-17570 HLICO10 120658740 AL031685 767 1-182 HLICO10 120 658740 AL031685 768 1-113 HLJBS28121 658742 AC026779 769 1-78 2390-2473 5457-7057 HLJBS28 121 658742AC008482 770 1-93 1668-1990 3077-4682 HLJBS28 121 658742 AC026779 7711-651 HLJBS28 121 658742 AC008482 772 1-807 HLMJB64 122 658699 AL034550773 1-107 122-1264 1513-4478 HLMJB64 122 658699 AL034550 774 1-147445-569 1012-1217 5637-5681 HLYDF73 124 566869 AL122127 775 1-583HLYGE16 125 651339 AC025594 776 1-272 301-388 531-1439 1461-3200 HLYGE16125 651339 AC073849 777 1-272 301-388 531-1439 1461-3200 HLYGE16 125651339 AC025594 778 1-337 HLYGE16 125 651339 AC073849 779 1-337 HMCFH60127 654853 AL122034 780 1-785 1072-3055 HMCFH60 127 654853 AC073394 7811-326 1898-2079 2460-2702 4498-4586 5598-7296 7560-7669 8015-84608479-8539 8918-9242 10451-10975 13375-13521 13561-15769 16055-18038HMCFH60 127 654853 AL160264 782 1-86 1101-2799 3063-3172 3518-39633982-4042 4421-4745 5954-6478 8877-9023 9063-11271 11557-13540 HMCFH60127 654853 AC073394 783 1-309 HMCFH60 127 654853 AC073394 784 1-577HMDAB29 128 584789 AC027264 785 1-147 HMDAB29 128 584789 AC068682 7861-153 HMDAB29 128 584789 AL354887 787 1-1433 HMDAB29 128 584789 AL157408788 1-1434 HMDAB29 128 584789 AL354887 789 1-577 HMDAB29 128 584789AL354887 790 1-196 HMDAB29 128 584789 AL157408 791 1-577 HMDAB29 128584789 AL157408 792 1-196 HMDAD44 129 566854 AC012370 793 1-1452813-4454 HMDAD44 129 566854 AC034121 794 1-1569 HMDAD44 129 566854AC012370 795 1-787 HMDAD44 129 566854 AC012370 796 1-622 HMIAK10 131562774 AP000817 797 1-1044 HMIAK10 131 562774 AC024177 798 1-1047HMIAK10 131 562774 AC011009 799 1-1047 HMIBF07 132 603528 AC022833 8001-1721 HMICI80 133 827318 AC008790 801 1-2743 HMICI80 133 827318AC066693 802 1-2743 HMICI80 133 827318 AC008790 803 1-377 HMICI80 133827318 AC066693 804 1-377 HMWBL03 139 822861 AC012052 805 1-130 548-7844520-4887 5112-6285 6741-6888 7577-7727 7951-8582 8927-10292 HMWBL03 139822861 AC011667 806 1-138 1281-1681 2270-2632 3070-3372 3865-39904407-4644 8378-8745 8970-10143 10599-10746 11435-11585 11809-1244012785-14150 HMWBL03 139 822861 AC012052 807 1-303 HNECW49 141 639117AC011864 808 1-522 HNECW49 141 639117 AC011864 809 1-607 HNECW49 141639117 AC011864 810 1-741 HNFGR08 143 825417 AC006369 811 1-1423 HNGAK51144 603910 AC013443 812 1-913 HNGAK51 144 603910 AC013443 813 1-406HNGAK51 144 603910 AC013443 814 1-297 HNGAM58 145 688114 AP000023 8151-104 106-313 HNGAM58 145 688114 AL353625 816 1-1881 2735-2808 3883-40435519-5602 5702-5845 6903-7175 9926-10120 11625-12238 12343-1267312887-13212 13309-13473 13482-13691 14962-15187 15799-16641 17298-1744718403-18517 21404-21557 22366-22603 22625-23551 25581-25730 26277-2668226765-26975 28188-28352 30552-30705 32576-32797 33083-33326 33654-3379134515-34643 36494-36685 37580-37916 38168-38308 38903-39515 41650-4174942020-42153 42920-43144 43218-43346 43937-44019 44180-44379 44623-4480044905-45050 45835-46036 47456-47567 HNGAM58 145 688114 AL136325 8171-308 HNGAM58 145 688114 AL078472 818 1-114 116-323 HNGAM58 145 688114AL049776 819 1-229 1654-1686 1809-1912 3738-4062 HNGAM58 145 688114AL031176 820 1-310 HNGAM58 145 688114 AL022329 821 1-255 HNGAM58 145688114 AL022302 822 1-97 591-698 4315-4635 HNGAM58 145 688114 AF111169823 1-287 HNGAM58 145 688114 AF001550 824 1-313 HNGAM58 145 688114AC009303 825 1-320 5298-5444 5797-6110 HNGAM58 145 688114 AC008958 8261-300 1024-1341 2289-2604 HNGAM58 145 688114 AC008554 827 1-306 HNGAM58145 688114 AC008101 828 1-115 165-466 966-1404 1633-1705 1926-20603344-3376 3578-3674 3887-4181 6025-6290 10101-10428 10551-1065411804-11921 12916-13092 14481-14684 15589-15954 16784-17082 17091-1730418309-18919 19343-19668 20553-20853 25924-26171 26200-26512 27209-27666HNGAM58 145 688114 AC008079 829 1-627 2228-2466 3557-3606 4115-42514459-4879 5931-6271 6478-6648 7457-7555 9361-9509 9666-9964 10062-1015112863-13276 13550-13664 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1-299 HNGAM58 145688114 AC002519 845 1-295 HNGAM58 145 688114 AC002476 846 1-40 4020-4364HNGAM58 145 688114 AC073220 847 1-311 766-4242 4507-4721 HNGAM58 145688114 AC019126 848 1-1000 1425-1500 3144-3288 4770-5081 5584-5635HNGAM58 145 688114 AC016772 849 1-209 HNGAM58 145 688114 AC015804 8501-139 HNGAM58 145 688114 AC007194 851 1-108 HNGAM58 145 688114 AC011740852 1-138 HNGAM58 145 688114 AL138740 853 1-323 HNGAM58 145 688114AL135839 854 1-115 161-358 HNGAM58 145 688114 AC022148 855 1-427 HNGAM58145 688114 Z82199 856 1-549 HNGAM58 145 688114 AJ239319 857 1-3351031-1609 1922-2102 4742-4918 4925-5059 HNGAM58 145 688114 AC023221 8581-129 HNGAM58 145 688114 AC011994 859 1-1939 HNGAM58 145 688114 AC011330860 1-139 HNGAM58 145 688114 AL121956 861 1-1881 2735-2808 3883-40435519-5602 5702-5845 6903-7175 9926-10120 11625-12238 12343-1267312887-13212 13309-13473 13482-13691 14962-15187 15799-16641 17298-1744718403-18517 21404-21557 22366-22603 22625-23551 25581-25730 26277-2668226765-26975 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5034-5269 5857-62646457-6771 6927-7080 7527-7850 7906-8247 HNGAM58 145 688114 AP000023 8721-83 HNGAM58 145 688114 AL353625 873 1-354 HNGAM58 145 688114 AL136325874 1-149 HNGAM58 145 688114 AL078472 875 1-83 HNGAM58 145 688114AL022329 876 1-636 HNGAM58 145 688114 AL022302 877 1-101 HNGAM58 145688114 AL022302 878 1-461 HNGAM58 145 688114 AF111169 879 1-101 HNGAM58145 688114 AC009303 880 1-222 HNGAM58 145 688114 AC008958 881 1-374HNGAM58 145 688114 AC008554 882 1-100 HNGAM58 145 688114 AC008101 8831-159 HNGAM58 145 688114 AC008079 884 1-159 HNGAM58 145 688114 AC008079885 1-73 300-338 801-1164 3740-5359 5459-6041 HNGAM58 145 688114AC008008 886 1-656 HNGAM58 145 688114 AC007666 887 1-90 145-413 HNGAM58145 688114 AC007324 888 1-214 1219-1829 HNGAM58 145 688114 AC007324 8891-300 HNGAM58 145 688114 AC006965 890 1-168 HNGAM58 145 688114 AC006946891 1-83 HNGAM58 145 688114 AC006548 892 1-83 HNGAM58 145 688114AC005598 893 1-279 HNGAM58 145 688114 AC005598 894 1-471 HNGAM58 145688114 AC005594 895 1-232 HNGAM58 145 688114 AC005221 896 1-3341068-1453 1964-2261 2279-2734 3142-3837 3844-4120 5655-6150 HNGAM58 145688114 AC004477 897 1-114 HNGAM58 145 688114 AC004460 898 1-327 HNGAM58145 688114 AC004019 899 1-90 145-413 HNGAM58 145 688114 AC002476 9001-232 HNGAM58 145 688114 AC073220 901 1-327 HNGAM58 145 688114 AC019126902 1-84 HNGAM58 145 688114 AC019126 903 1-510 HNGAM58 145 688114AC016772 904 1-90 270-523 1613-1654 2621-2727 4508-4585 4669-47475079-5131 HNGAM58 145 688114 AC016772 905 1-554 HNGAM58 145 688114AC015804 906 1-456 HNGAM58 145 688114 AC015804 907 1-157 HNGAM58 145688114 AC011740 908 1-382 1357-2450 4643-5158 HNGAM58 145 688114AC011740 909 1-125 HNGAM58 145 688114 AL135839 910 1-87 HNGAM58 145688114 AC022148 911 1-780 HNGAM58 145 688114 Z82199 912 1-1459 HNGAM58145 688114 Z82199 913 1-396 HNGAM58 145 688114 AJ239319 914 1-129HNGAM58 145 688114 AC023221 915 1-130 HNGAM58 145 688114 AC011330 9161-465 HNGAM58 145 688114 AL121956 917 1-354 HNGAM58 145 688114 AL354950918 1-485 HNGAM58 145 688114 AL354950 919 1-116 HNGAM58 145 688114AL160471 920 1-244 834-940 969-1079 1473-1628 HNGAM58 145 688114AL160471 921 1-1366 HNGAM58 145 688114 AC021669 922 1-786 HNGAM58 145688114 AL157832 923 1-485 HNGAM58 145 688114 AL157832 924 1-116 HNGAM58145 688114 AC004971 925 1-913 HNGDX18 146 1145071 AL391069 926 1-1403HNGDX18 146 1145071 AL158846 927 1-193 208-577 894-1167 1401-16291918-3320 4039-4082 9400-10337 HNGDX18 146 1145071 AL391069 928 1-274HNGDX18 146 1145071 AL158846 929 1-117 HNGEQ75 147 535723 AC009729 9301-1899 HNGEQ75 147 535723 AC009729 931 1-104 HNGFR54 148 695748 AC007316932 1-456 HNGFR54 148 695748 AC007316 933 1-260 HNGHZ69 150 899289AC011239 934 1-1190 HNGHZ69 150 899289 AC011239 935 1-432 HNGKT41 151836061 AC008581 936 1-1099 HNGNO53 153 836063 AC023387 937 1-869 HNGNO53153 836063 AL355500 938 1-851 HNGPJ25 154 834942 AP002781 939 1-1472HNHGK22 156 597451 AC073193 940 1-898 HNHGK22 156 597451 AC073193 9411-306 HNHKV56 158 800877 AC009396 942 1-1605 HODBB70 160 520196 AC006322943 1-561 HODBB70 160 520196 AC073110 944 1-561 HODBB70 160 520196AC025553 945 1-561 HODBB70 160 520196 AC006322 946 1-1741 HODBB70 160520196 AC006322 947 1-354 HODBB70 160 520196 AC073110 948 1-1741 HODBB70160 520196 AC073110 949 1-354 HOUDE92 165 580866 AC005865 950 1-173553-629 1941-2042 2757-2891 3294-3378 4606-5498 5550-8125 HOVBD85 166827362 AC026132 951 1-1111 HOVBD85 166 827362 AC026132 952 1-315 HPCAB41167 758003 AC022702 953 1-2582 HPCAB41 167 758003 AC022702 954 1-7011327-1761 2233-2581 2798-3345 HPCAB41 167 758003 AC022702 955 1-262HPFCI36 169 855966 AL161652 956 1-174 313-4710 HPFDI37 170 862056AC000090 957 1-29 566-712 1355-1425 3075-3241 3725-3806 4295-43575382-5571 6510-7016 7981-8321 HPJCW58 172 612866 AC024735 958 1-1160HPMFH77 173 702014 AL357792 959 1-78 1506-1910 2138-2352 3564-36553894-3990 4679-4802 6730-6826 7263-7346 7463-7531 8845-8944 9220-940711682-11793 12453-13057 13114-13869 13880-14347 14370-17543 17664-20113HPMFH77 173 702014 AC012043 960 1-78 1506-1910 2138-2352 3564-36553894-3990 4679-4802 6730-6826 7263-7346 7463-7531 8845-8944 9220-940711682-11793 12453-13057 13114-13869 13880-14347 14370-17540 17661-20110HPMFH77 173 702014 AL357792 961 1-423 HPMFH77 173 702014 AL357792 9621-974 HPMFH77 173 702014 AC012043 963 1-974 HPMFH77 173 702014 AC012043964 1-423 HPQCB83 174 740761 AC069100 965 1-2234 HRADA42 178 827302AC011890 966 1-943 1079-1636 2154-2473 3555-4008 4292-4439 6963-71548254-8537 8592-8985 HRADA42 178 827302 AC011890 967 1-478 HRADF49 179866481 AC068946 968 1-142 359-1108 1191-1345 1445-2140 2314-29353040-3156 3395-4126 4311-4460 4749-5820 HRADF49 179 866481 AC060820 9691-142 359-1109 1193-1348 1448-2142 2318-2944 3056-3166 3405-41364321-4472 4762-5836 HRADF49 179 866481 AC068946 970 1-812 1124-12631281-2283 2470-2572 2752-2935 3851-3974 4153-4548 4602-4810 4980-51115262-5346 5434-5498 5609-5695 5871-5930 6448-6487 HRADF49 179 866481AC060820 971 1-686 HRDDQ39 181 840405 AC009152 972 1-755 HRDER22 182688056 AC021153 973 1-554 HRDER22 182 688056 AC021153 974 1-205 HRDFK37184 840381 AL360017 975 1-1274 HSAVA08 186 580870 AC009030 976 1-1052HSAVA08 186 580870 AC009030 977 1-431 HSAVW42 187 637660 AC021117 9781-865 HSAVW42 187 637660 AC021117 979 1-336 397-651 HSAVW42 187 637660AC021117 980 1-185 HSHBF76 190 715838 AC009000 981 1-479 1244-14081653-1763 1845-1991 2826-3064 3330-3422 3438-3788 HSHBF76 190 715838AC009000 982 1-128 HSHBF76 190 715838 AC009000 983 1-36 1068-13291498-2123 3160-3211 HSJBY32 192 702020 AC060812 984 1-834 1161-2914HSJBY32 192 702020 AC060812 985 1-328 1564-1799 2800-2937 3007-30454054-4838 5145-5257 HSJBY32 192 702020 AC060812 986 1-659 700-1802HSKDR27 193 580874 AC008742 987 1-50 1016-1321 1979-2220 2313-3310HSKDR27 193 580874 AC008742 988 1-495 HSNAP85 194 784054 AC007541 9891-94 2363-2658 3490-3979 4019-7173 HSQDO85 196 853393 AL022313 990 1-3373275-3416 3702-3761 3789-4346 4678-4817 5426-5518 6130-6208 7676-81618344-8443 8722-8841 9247-10011 10488-10650 11981-12464 12622-1271112791-13240 13285-13619 14613-15627 15868-16325 16558-17064 17148-1751717623-17912 17963-18564 HSQDO85 196 853393 AL022313 991 1-140 HSRBE06197 871264 AP000330 992 1-1628 HSRBE06 197 871264 AP000330 993 1-526HSSEA64 199 853395 AC005865 994 1-173 553-629 1941-2042 2757-28913294-3378 4606-5498 5550-8125 HSSEF77 200 658725 AC005041 995 1-6887-493 711-838 997-1167 2227-2960 3326-4641 4768-5786 HSSEF77 200 658725AC005041 996 1-2920 3439-3667 3839-4332 HSSEF77 200 658725 AC005041 9971-143 HT1SC27 203 630647 AP001077 998 1-2841 HT1SC27 203 630647 AP001077999 1-758 HT1SC27 203 630647 AP001077 1000 1-625 HT4FV41 204 853400AC011547 1001 1-170 793-936 2771-3041 3691-3788 5141-5252 5755-60306325-6407 7214-7551 8653-8940 9033-9136 9428-9907 11266-1165912082-12263 13451-13544 13664-13699 13769-13936 14571-14761 14897-1499715135-17127 HT4FV41 204 853400 AC005331 1002 1-88 224-324 462-2454HT4FV41 204 853400 AC023470 1003 1-80 204-242 313-477 1213-13001436-1536 1673-3658 HT4FV41 204 853400 AC005331 1004 1-607 HT4FV41 204853400 AC023470 1005 1-606 HTEGS11 209 862066 AC018762 1006 1-2894HTEHU59 210 840385 AP001003 1007 1-3207 HTEHU59 210 840385 AP001557 10081-3206 HTEHU59 210 840385 AP001156 1009 1-3207 HTEHU59 210 840385AP001003 1010 1-863 HTEHU59 210 840385 AP001003 1011 1-1399 1504-19481956-2672 2761-2905 3007-3135 3290-3445 3537-3653 3746-3913 4010-41314251-4428 HTEHU59 210 840385 AP001557 1012 1-863 HTEHU59 210 840385AP001557 1013 1-1395 1500-1944 1952-2667 2757-2900 3002-3130 3285-3439HTEHU59 210 840385 AP001156 1014 1-1396 1502-1945 1953-2668 HTEHU59 210840385 AP001156 1015 1-863 HTEJD29 211 695798 AL354733 1016 1-1292HTEJD29 211 695798 AC007943 1017 1-1292 HTEJD29 211 695798 AL354733 10181-184 HTEJD29 211 695798 AL354733 1019 1-59 1212-1284 1905-19562351-2840 4126-5105 5892-6298 6726-7122 7204-7713 7747-7932 HTHBZ06 215832477 AC068768 1020 1-835 HTLAP64 216 603913 AC004556 1021 1-16682186-3003 3754-4253 4400-4483 5365-5868 8438-8508 8913-9031 9113-9151HTLAP64 216 603913 AC051649 1022 1-1669 2187-3004 3755-4254 4401-44845367-5870 8558-8628 9033-9151 9233-9273 HTLBT80 217 840045 AL133227 10231-51 476-521 842-1226 1375-1490 3745-4016 4046-4229 4430-4855 5300-60536598-6883 7406-7446 7461-8437 8550-8681 8888-8919 8943-9353 9458-95449834-10607 11550-11629 12196-12374 13532-14886 HTLBT80 217 840045AL133227 1024 1-32 712-1071 3453-3870 4197-4326 4639-4751 5131-52025588-5638 7454-8108 8670-8767 9511-9692 9754-10134 11109-1122612456-12607 15237-15316 18143-18311 18429-18478 20682-20982 20988-2129522686-23061 23358-23495 24076-24612 25196-25334 26760-26926 27041-2715227271-27379 27697-28289 29024-29340 29761-29840 31168-32681 HTLDU78 218637702 AC011444 1025 1-1305 HTLDU78 218 637702 AC011444 1026 1-285HTLDU78 218 637702 AC011444 1027 1-274 HTLFA13 220 535937 AC022007 10281-1127 HTLFA13 220 535937 AC021995 1029 1-1115 HTLFA13 220 535937AC007783 1030 1-1144 HTLFA13 220 535937 AC022007 1031 1-1729 HTLFA13 220535937 AC022007 1032 1-179 184-696 HTLFA13 220 535937 AC021995 10331-106 132-190 674-831 1456-1588 3423-4270 4811-4933 5118-5304 HTLFA13220 535937 AC021995 1034 1-179 184-696 894-945 HTLFA13 220 535937AC007783 1035 1-169 180-258 681-859 864-1376 3240-3503 HTLFA13 220535937 AC007783 1036 1-1729 HTLGI89 221 835069 AC048342 1037 1-130HTLGI89 221 835069 AC009453 1038 1-143 HTLGI89 221 835069 AC022231 10391-151 HTLGI89 221 835069 AC009524 1040 1-151 HTLGI89 221 835069 AC0483421041 1-118 HTOAM11 224 664508 AC002369 1042 1-586 2559-2651 3329-34263756-5088 HTOAM11 224 664508 AP001486 1043 1-1191 HTOAM11 224 664508AP000875 1044 1-1192 HTOAM11 224 664508 AC002369 1045 1-228 HTOAM11 224664508 AP001486 1046 1-711 HTOAM11 224 664508 AP001486 1047 1-374HTOAM11 224 664508 AP000875 1048 1-710 HTODH83 225 580884 AC012046 10491-1972 HTODH83 225 580884 AC012046 1050 1-105 HTSFJ32 227 637720AC015734 1051 1-80 562-915 925-4400 HTSFJ32 227 637720 AC015734 10521-463 HTSFJ32 227 637720 AC015734 1053 1-359 HTTEE41 229 840950 AC0189211054 1-92 318-578 837-912 1091-1249 1321-1387 1862-2192 2485-25792708-2831 3685-4257 4547-5127 5811-6037 6562-7076 7541-7678 8069-819110100-10207 11102-11688 11721-11847 12201-12335 12532-12641 12888-1299113027-13546 13637-16146 HTTEE41 229 840950 AC018921 1055 1-100 HTWEH94231 561680 AC004858 1056 1-1349 1370-1744 HTWEH94 231 561680 AC0048581057 1-94 HTWEH94 231 561680 AC004858 1058 1-199 HTXDC77 232 844258AC004182 1059 1-2744 2917-3357 HTXDC77 232 844258 AC018433 1060 1-27442917-3357 HTXET11 234 581521 AC011802 1061 1-984 HTXET11 234 581521AC025414 1062 1-984 HTXET11 234 581521 AC011802 1063 1-36 836-9644059-5438 6005-6176 6789-7120 7124-7588 7735-7827 7925-8770 9057-9545HTXET11 234 581521 AC025414 1064 1-36 836-964 4059-5438 6002-61736786-7117 7121-7585 7732-7809 HTXFA72 235 853410 AP001812 1065 1-1015HTXFA72 235 853410 AP000822 1066 1-1015 HTXFA72 235 853410 AP001812 10671-130 HTXFA72 235 853410 AP000822 1068 1-527 HTXJY08 236 637774 AC0059621069 1-2075 HTXJY08 236 637774 AC004757 1070 1-2075 HTXJY08 236 637774AC005962 1071 1-478 HTXJY08 236 637774 AC005962 1072 1-1011 HTXJY08 236637774 AC004757 1073 1-478 HTXJY08 236 637774 AC004757 1074 1-1011HUKBT67 238 844446 AC073594 1075 1-391 604-856 1324-1453 1957-20542407-2953 3443-5533 HUKBT67 238 844446 AC076968 1076 1-392 605-8581326-1455 1959-2056 2409-2956 3447-5543 HUKBT67 238 844446 AC010892 10771-391 604-857 1325-1454 1958-2055 2408-2955 3446-5538 HUKBT67 238 844446AC068986 1078 1-391 604-857 1325-1454 1958-2055 2408-2955 3445-5537HUKBT67 238 844446 AC010892 1079 1-436 HUKBT67 238 844446 AC010892 10801-368 HUKBT67 238 844446 AC068986 1081 1-436 HUSCJ14 240 894699 AC0070401082 1-149 394-889 1061-1139 2097-2249 2852-3007 5021-5089 5217-59196119-8896 HUSCJ14 240 894699 AC007040 1083 1-854 HUSCJ14 240 894699AC007040 1084 1-397 HUSGU40 242 684975 AC072032 1085 1-364 HUSGU40 242684975 AC022305 1086 1-686 HUSGU40 242 684975 AC078916 1087 1-364HUSGU40 242 684975 AC072032 1088 1-288 HUSGU40 242 684975 AC078916 10891-288 HUSIR18 243 762858 AC068055 1090 1-149 HUSIR18 243 762858 AC0222311091 1-151 HUSIR18 243 762858 AC010694 1092 1-202 HUSIR18 243 762858AL160163 1093 1-258 1798-4171 HUSIR18 243 762858 AC027300 1094 1-158HUSIR18 243 762858 AC073047 1095 1-170 HUSIR18 243 762858 AC009524 10961-151 HUSIR18 243 762858 AC068055 1097 1-77 HUSIR18 243 762858 AC0106941098 1-77 HUSIR18 243 762858 AL160163 1099 1-117 HWDAC26 245 821335AC004947 1100 1-1669 HWDAJ01 246 794016 AC015551 1101 1-670 HWDAJ01 246794016 AC019214 1102 1-670 HYABC84 249 865064 AL132825 1103 1-25122604-2740 2974-3241 1-2512 2604-2740 2974-3241 HYABC84 249 865064AL132825 1104 1-553 1-553 1059-1263 1059-1263 3121-3476 3121-34765284-5734 5284-5734 6284-6513 6284-6513 6786-7426 6786-7426 8674-87338674-8733 10656-10933 10656-10933 11453-11555 11453-11555 12991-1307912991-13079 13839-14281 13839-14281 14527-14827 14527-14827 15156-1568515156-15685 15835-16046 15835-16046 16166-16604 16166-16604 16736-1956616736-19566 19658-19794 19658-19794 20028-20295 20028-20295 HYABC84 249865064 AL132825 1105 1-188 1-188 HE2CA60 250 888705 AC005921 1106 1-74276-1076 1472-2160 3055-3389 3769-3898 4143-4288 4322-4697 4699-47726745-6851 7692-9044 9581-9743 13540-17646 1-74 276-1076 1472-21603055-3389 3769-3898 4143-4288 4322-4697 4699-4772 6745-6851 7692-90449581-9743 13540-17646 HE2CA60 250 888705 AC005921 1107 1-1466 1-1466HE8FD92 252 901142 AL359176 1108 1-2410 1-2410 1-2410 2420-42262420-4226 2420-4226 HE8FD92 252 901142 AL139152 1109 1-826 863-20632125-4935 4945-6753 1-826 863-2063 2125-4935 4945-6753 1-826 863-20632125-4935 4945-6753 1-826 863-2063 2125-4935 4945-6753 HE8FD92 252901142 AL109937 1110 1-168 233-930 1572-1748 2463-3391 HE8FD92 252901142 AC027209 1111 1-1201 1-1201 1-1201 1263-1531 1263-1531 1263-15311648-5860 1648-5860 1648-5860 HE8FD92 252 901142 AL356004 1112 1-10521062-2871 HE8FD92 252 901142 AL139152 1113 1-560 760-1714 1740-36443736-4319 4872-4998 1-560 760-1714 1740-3644 3736-4319 4872-4998 1-560760-1714 1740-3644 3736-4319 4872-4998 1-560 760-1714 1740-36443736-4319 4872-4998 HE8FD92 252 901142 AL109937 1114 1-437 HE8FD92 252901142 AC027209 1115 1-560 1-560 1-560 747-1721 747-1721 747-17211875-3650 1875-3650 1875-3650 3698-4325 3698-4325 3698-4325 4657-46934657-4693 4657-4693 4879-5008 4879-5008 4879-5008 HE8FD92 252 901142AC027209 1116 1-423 1-423 1-423 HE8FD92 252 901142 AL356004 1117 1-560

Table 1D: The polynucleotides or polypeptides, or agonists orantagonists of the present invention can be used in assays to test forone or more biological activities. If these polynucleotides andpolypeptides do exhibit activity in a particular assay, it is likelythat these molecules may be involved in the diseases associated with thebiological activity. Thus, the polynucleotides or polypeptides, oragonists or antagonists could be used to treat the associated disease.

The present invention encompasses methods of detecting, preventing,diagnosing, prognosticating, treating, and/or ameliorating a disease ordisorder. In preferred embodiments, the present invention encompasses amethod of treating a cardiovascular disease or disorder comprisingadministering to a patient in which such detection, treatment,prevention, and/or amelioration is desired a protein, nucleic acid, orantibody of the invention (or fragment or variant thereof) in an amounteffective to detect, prevent, diagnose, prognosticate, treat, and/orameliorate the cardiovascular disease or disorder.

In another embodiment, the present invention also encompasses methods ofdetecting, preventing, diagnosing, prognosticating, treating, and/orameliorating a cardiovascular disease or disorder; comprisingadministering to a patient combinations of the proteins, nucleic acids,or antibodies of the invention (or fragments or variants thereof),sharing similar indications as shown in the corresponding rows in Column3 of Table 1D.

Table 1D provides information related to biological activities forpolynucleotides and polypeptides of the invention (including antibodies,agonists, and/or antagonists thereof). Table 1D also providesinformation related to assays which may be used to test polynucleotidesand polypeptides of the invention (including antibodies, agonists,and/or antagonists thereof) for the corresponding biological activities.The first column (“Gene No.”) provides the gene number in theapplication for each clone identifier. The second column (“cDNA CloneID:”) provides the unique clone identifier for each clone as previouslydescribed and indicated in Table 1A through Table 1D. The third column(“AA SEQ ID NO:Y”) indicates the Sequence Listing SEQ ID Number forpolypeptide sequences encoded by the corresponding cDNA clones (also asindicated in Tables 1A, Table 1B, and Table 2). The fourth column(“Biological Activity”) indicates a biological activity corresponding tothe indicated polypeptides (or polynucleotides encoding saidpolypeptides). The fifth column (“Exemplary Activity Assay”) furtherdescribes the corresponding biological activity and also providesinformation pertaining to the various types of assays which may beperformed to test, demonstrate, or quantify the corresponding biologicalactivity.

Table 1D describes the use of, inter alia, FMAT technology for testingor demonstrating-various biological activities. Fluorometric microvolumeassay technology (FMAT) is a fluorescence-based system which provides ameans to perform nonradioactive cell- and bead-based assays to detectactivation of cell signal transduction pathways. This technology wasdesigned specifically for ligand binding and immunological assays. Usingthis technology, fluorescent cells or beads at the bottom of the wellare detected as localized areas of concentrated fluorescence using adata processing system. Unbound flurophore comprising the backgroundsignal is ignored, allowing for a wide variety of homogeneous assays.FMAT technology may be used for peptide ligand binding assays,immunofluorescence, apoptosis, cytotoxicity, and bead-basedimmunocapture assays. See, Miraglia S et. al., “Homogeneous cell andbead based assays for highthroughput screening using flourometricmicrovolume assay technology,” Journal of Biomolecular Screening;4:193-204 (1999). In particular, FMAT technology may be used to test,confirm, and/or identify the ability of polypeptides (includingpolypeptide fragments and variants) to activate signal transductionpathways. For example, FMAT technology may be used to test, confirm,and/or identify the ability of polypeptides to upregulate production ofimmunomodulatory proteins (such as, for example, interleukins, GM-CSF,Rantes, and Tumor Necrosis factors, as well as other cellular regulators(e.g. insulin)).

Table 1D also describes the use of kinase assays for testing,demonstrating, or quantifying biological activity. In this regard, thephosphorylation and de-phosphorylation of specific amino acid residues(e.g. Tyrosine, Serine, Threonine) on cell-signal transduction proteinsprovides a fast, reversible means for activation and de-activation ofcellular signal transduction pathways. Moreover, cell signaltransduction via phosphorylation/de-phosphorylation is crucial to theregulation of a wide variety of cellular processes (e.g. proliferation,differentiation, migration, apoptosis, etc.). Accordingly, kinase assaysprovide a powerful tool useful for testing, confirming, and/oridentifying polypeptides (including polypeptide fragments and variants)that mediate cell signal transduction events via proteinphosphorylation. See e.g., Forrer, P., Tamaskovic R., and Jaussi, R.“Enzyme-Linked Immunosorbent Assay for Measurement of JNK, ERK, and p38Kinase Activities” Biol. Chem 379(8-9): 1101-1110 (1998). LENGTHY TABLEREFERENCED HERE US20070032414A1-20070208-T00001 Please refer to the endof the specification for access instructions.Table 1E

Polynucleotides encoding polypeptides of the present invention can beused in assays to test for one or more biological activities. One suchbiological activity which may be tested includes the ability ofpolynucleotides and polypeptides of the invention to stimulateup-regulation or down-regulation of expression of particular genes andproteins. Hence, if polynucleotides and polypeptides of the presentinvention exhibit activity in altering particular gene and proteinexpression patterns, it is likely that these polynucleotides andpolypeptides of the present invention may be involved in, or capable ofeffecting changes in, diseases associated with the altered gene andprotein expression profiles. Hence, polynucleotides, polypeptides, orantibodies of the present invention could be used to treat saidassociated diseases.

TaqMan® assays may be performed to assess the ability of polynucleotides(and polypeptides they encode) to alter the expression pattern ofparticular “target” genes. TaqMan® reactions are performed to evaluatethe ability of a test agent to induce or repress expression of specificgenes in different cell types. TaqMan® gene expression quantificationassays (“TaqMan® assays”) are well known to, and routinely performed by,those of ordinary skill in the art. TaqMan® assays are performed in atwo step reverse transcription/polymerase chain reaction (RT-PCR). Inthe first (RT) step, cDNA is reverse transcribed from total RNA samplesusing random hexamer primers. In the second (PCR) step, PCR products aresynthesized from the cDNA using gene specific primers.

To quantify gene expression the Taqman® PCR reaction exploits the 5′nuclease activity of AmpliTaq Gold® DNA Polymerase to cleave a Taqman®probe (distinct from the primers) during PCR. The Taqman® probe containsa reporter dye at the 5′-end of the probe and a quencher dye at the 3′end of the probe. When the probe is intact, the proximity of thereporter dye to the quencher dye results in suppression of the reporterfluorescence. During PCR, if the target of interest is present, theprobe specifically anneals between the forward and reverse primer sites.AmpliTaq Fold DNA Polymerase then cleaves the probe between the reporterand quencher when the probe hybridizes to the target, resulting inincreased fluorescence of the reporter (see FIG. 2). Accumulation of PCRproducts is detected directly by monitoring the increase in fluorescenceof the reporter dye.

After the probe fragments are displaced from the target, polymerizationof the strand continues. The 3′-end of the probe is blocked to preventextension of the probe during PCR. This process occurs in every cycleand does not interfere with the exponential accumulation of product. Theincrease in fluorescence signal is detected only if the target sequenceis complementary to the probe and is amplified during PCR. Because ofthese requirements, any nonspecific amplification is not detected.

For test sample preparation, vector controls or constructs containingthe coding sequence for the gene of interest are transfected into cells,such as for example 293T cells, and supernatants collected after 48hours. For cell treatment and RNA isolation, multiple primary humancells or human cell lines are used; such cells may include but are notlimited to, Normal Human Dermal Fibroblasts, Aortic Smooth Muscle, HumanUmbilical Vein Endothelial Cells, HepG2, Daudi, Jurkat, U937, Caco, andTHP-1 cell lines. Cells are plated in growth media and growth isarrested by culturing without media change for 3 days, or by switchingcells to low serum media and incubating overnight. Cells are treated for1, 6, or 24 hours with either vector control supernatant or samplesupernatant (or purified/partially purified protein preparations inbuffer). Total RNA is isolated; for example, by using Trizol extractionor by using the Ambion RNAqueous(I)-4PCR RNA isolation system.Expression levels of multiple genes are analyzed using TAQMAN, andexpression in the test sample is compared to control vector samples toidentify genes induced or repressed. Each of the above describedtechniques are well known to, and routinely performed by, those ofordinary skill in the art.

Table BE indicates particular disease classes and preferred indicationsfor which polynucleotides, polypeptides, or antibodies of the presentinvention may be used in detecting, diagnosing, preventing, treatingand/or ameliorating said diseases and disorders based on “target” geneexpression patterns which may be up- or down-regulated bypolynucleotides (and the encoded polypeptides) corresponding to eachindicated cDNA Clone ID (shown in Table 1E, Column 2).

Thus, in preferred embodiments, the present invention encompasses amethod of detecting, diagnosing, preventing, treating, and/orameliorating a disease or disorder listed in the “Disease Class” and/or“Preferred Indication” columns of Table 1E; comprising administering toa patient in which such detection, diagnosis, prevention, or treatmentis desired a protein, nucleic acid, or antibody of the invention (orfragment or variant thereof) in an amount effective to detect, diagnose,prevent, treat, or ameliorate the disease or disorder. The first andsecond columns of Table 1D show the “Gene No.” and “cDNA Clone ID No.”,respectively, indicating certain nucleic acids and proteins (orantibodies against the same) of the invention (including polynucleotide,polypeptide, and antibody fragments or variants thereof) that may beused in detecting, diagnosing, preventing, treating, or ameliorating thedisease(s) or disorder(s) indicated in the corresponding row in the“Disease Class” or “Preferred Indication” Columns of Table BE.

In another embodiment, the present invention also encompasses methods ofdetecting, diagnosing, preventing, treating, or ameliorating a diseaseor disorder listed in the “Disease Class” or “Preferred Indication”Columns of Table 1E; comprising administering to a patient combinationsof the proteins, nucleic acids, or antibodies of the invention (orfragments or variants thereof), sharing similar indications as shown inthe corresponding rows in the “Disease Class” or “Preferred Indication”Columns of Table 1E.

The “Disease Class” Column of Table 1E provides a categorizeddescriptive heading for diseases, disorders, and/or conditions (morefully described below) that may be detected, diagnosed, prevented,treated, or ameliorated by a protein, nucleic acid, or antibody of theinvention (or fragment or variant thereof).

The “Preferred Indication” Column of Table 1E describes diseases,disorders, and/or conditions that may be detected, diagnosed, prevented,treated, or ameliorated by a protein, nucleic acid, or antibody of theinvention (or fragment or variant thereof).

The “Cell Line” and “Exemplary Targets” Columns of Table 1E indicateparticular cell lines and target genes, respectively, which may showaltered gene expression patterns (i.e., up- or down-regulation of theindicated target gene) in Taqman assays, performed as described above,utilizing polynucleotides of the cDNA Clone ID shown in thecorresponding row. Alteration of expression patterns of the indicated“Exemplary Target” genes is correlated with a particular “Disease Class”and/or “Preferred Indication” as shown in the corresponding row underthe respective column headings.

The “Exemplary Accessions” Column indicates GenBank Accessions(available online through the National Center for BiotechnologyInformation (NCBI) at http://www.ncbi.nlm.nih.gov/) which correspond tothe “Exemplary Targets” shown in the adjacent row.

The recitation of “Cancer” in the “Disease Class” Column indicates thatthe corresponding nucleic acid and protein, or antibody against thesame, of the invention (or fragment or variant thereof) may be used forexample, to detect, diagnose, prevent, treat, and/or ameliorateneoplastic diseases and/or disorders (e.g., leukemias, cancers, etc., asdescribed below under “Hyperproliferative Disorders”).

The recitation of “Immune” in the “Disease Class” column indicates thatthe corresponding nucleic acid and protein, or antibody against thesame, of the invention (or fragment or variant thereof), may be used forexample, to detect, diagnose, prevent, treat, and/or ameliorate diseasesand/or disorders relating to neoplastic diseases (e.g., as describedbelow under “Hyperproliferative Disorders”), blood disorders (e.g., asdescribed below under “Immune Activity” “Cardiovascular Disorders”and/or “Blood-Related Disorders”), and infections (e.g., as describedbelow under “Infectious Disease”).

The recitation of “Angiogenesis” in the “Disease Class” column indicatesthat the corresponding nucleic acid and protein, or antibody against thesame, of the invention (or fragment or variant thereof), may be used forexample, to detect, diagnose, treat, prevent, and/or ameliorate diseasesand/or disorders relating to neoplastic diseases (e.g., as describedbelow under “Hyperproliferative Disorders”), diseases and/or disordersof the cardiovascular system (e.g., as described below under“Cardiovascular Disorders”), diseases and/or disorders involvingcellular and genetic abnormalities (e.g., as described below under“Diseases at the Cellular Level”), diseases and/or disorders involvingangiogenesis (e.g., as described below under “Anti-AngiogenesisActivity”), to promote or inhibit cell or tissue regeneration (e.g., asdescribed below under “Regeneration”), or to promote wound healing(e.g., as described below under “Wound Healing and Epithelial CellProliferation”).

The recitation of “Diabetes” in the “Disease Class” column indicatesthat the corresponding nucleic acid and protein, or antibody against thesame, of the invention (or fragment or variant thereof), may be used forexample, to detect, diagnose, treat, prevent, and/or ameliorate diabetes(including diabetes mellitus types I and II), as well as diseases and/ordisorders associated with, or consequential to, diabetes (e.g. asdescribed below under “Endocrine Disorders,” “Renal Disorders,” and“Gastrointestinal Disorders”). TABLE 1E Gene cDNA Disease ExemplaryExemplary No. CloneID Class Preferred Indications Cell Line TargetsAccessions 40 HCEGG08 Angiogenesis Highly preferred indications includediagnosis, prevention, AOSMC Vegf1 gb|AF024710|AF024710 treatment,and/or amelioration of diseases and disorders involving angiogenesis,wound healing, neoplasia (particularly including, but not limited to,tumor metastases), and cardiovascular diseases and disorders; asdescribed herein under the headings “Hyperproliferative Disorders,”“Regeneration,” “Anti-Angiogenesis Activity,” “Diseases at the CellularLevel,” and “Wound Healing and Epithelial Cell Proliferation.”(AOSMCcells are aortic smooth muscle cells). 40 HCEGG08 Angiogenesis Highlypreferred indications include diagnosis, prevention, Caco-2 Flt1gb|AF063657|AF063657 treatment, and/or amelioration of diseases anddisorders involving angiogenesis, wound healing, neoplasia (particularlyincluding, but not limited to, tumor metastases), and cardiovasculardiseases and disorders; as described herein under the headings“Hyperproliferative Disorders,” “Regeneration,” “Anti-AngiogenesisActivity,” “Diseases at the Cellular Level,” and “Wound Healing andEpithelial Cell Proliferation.”(The Caco-2 cell line is a humancolorectal adenocarcinoma cell line available through the ATCC as cellline number HTB-37). 40 HCEGG08 Angiogenesis Highly preferredindications include diagnosis, prevention, HEK293 ICAM gb|X06990|HSICAM1treatment, and/or amelioration of diseases and disorders involvingangiogenesis, wound healing, neoplasia (particularly including, but notlimited to, tumor metastases), and cardiovascular diseases anddisorders; as described herein under the headings “HyperproliferativeDisorders,” “Regeneration,” “Anti-Angiogenesis Activity,” “Diseases atthe Cellular Level,” and “Wound Healing and Epithelial CellProliferation.”(The HEK293 cell line is a human embryonal kidneyepithelial cell line available through the ATCC as cell line numberCRL-1573). 40 HCEGG08 Angiogenesis Highly preferred indications includediagnosis, prevention, HUVEC PAI gb|X12701|HSENDPAI treatment, and/oramelioration of diseases and disorders involving angiogenesis, woundhealing, neoplasia (particularly including, but not limited to, tumormetastases), and cardiovascular diseases and disorders; as describedherein under the headings “Hyperproliferative Disorders,”“Regeneration,” “Anti-Angiogenesis Activity,” “Diseases at the CellularLevel,” and “Wound Healing and Epithelial Cell Proliferation.”(HUVECcells are human umbilical vein endothelial cells). 40 HCEGG08Angiogenesis Highly preferred indications include diagnosis, prevention,Liver ICAM gb|X06990|HSICAM1 treatment, and/or amelioration of diseasesand disorders involving angiogenesis, wound healing, neoplasia(particularly including, but not limited to, tumor metastases), andcardiovascular diseases and disorders; as described herein under theheadings “Hyperproliferative Disorders,” “Regeneration,”“Anti-Angiogenesis Activity,” “Diseases at the Cellular Level,” and“Wound Healing and Epithelial Cell Proliferation.” 40 HCEGG08Angiogenesis Highly preferred indications include diagnosis, prevention,NHDF TSP-1 gb|X04665|HSTHROMR treatment, and/or amelioration of diseasesand disorders Vegf1 gb|AF024710|AF024710 involving angiogenesis, woundhealing, neoplasia (particularly including, but not limited to, tumormetastases), and cardiovascular diseases and disorders; as describedherein under the headings “Hyperproliferative Disorders,”“Regeneration,” “Anti-Angiogenesis Activity,” “Diseases at the CellularLevel,” and “Wound Healing and Epithelial Cell Proliferation.”(NHDFcells are normal human dermal fibroblasts). 40 HCEGG08 AngiogenesisHighly preferred indications include diagnosis, prevention, SK-N-MCTSP-1 gb|X04665|HSTHROMR treatment, and/or amelioration of diseases anddisorders neuro- VCAM gb|A30922|A30922 involving angiogenesis, woundhealing, neoplasia (particularly blastoma Vegf1 gb|AF024710|AF024710including, but not limited to, tumor metastases), and cardiovasculardiseases and disorders; as described herein under the headings“Hyperproliferative Disorders,” “Regeneration,” “Anti-AngiogenesisActivity,” “Diseases at the Cellular Level,” and “Wound Healing andEpithelial Cell Proliferation.”(The SK-N-MC neuroblastoma cell line is acell line derived from human brain tissue available through the ATCC ascell line number HTB-10). 40 HCEGG08 Angiogenesis Highly preferredindications include diagnosis, prevention, THP1 VCAM gb|A30922|A30922treatment, and/or amelioration of diseases and disorders Vegf1gb|AF024710|AF024710 involving angiogenesis, wound healing, neoplasia(particularly including, but not limited to, tumor metastases), andcardiovascular diseases and disorders; as described herein under theheadings “Hyperproliferative Disorders,” “Regeneration,”“Anti-Angiogenesis Activity,” “Diseases at the Cellular Level,” and“Wound Healing and Epithelial Cell Proliferation.”(The THP-1 cell lineis a human monocyte cell line available through the ATCC as cell linenumber TIB- 202). 197 HTEEW69 Angiogenesis Highly preferred indicationsinclude diagnosis, prevention, Caco-2 iNOS gb|X85761|HSNOS2E3 treatment,and/or amelioration of diseases and disorders involving angiogenesis,wound healing, neoplasia (particularly including, but not limited to,tumor metastases), and cardiovascular diseases and disorders; asdescribed herein under the headings “Hyperproliferative Disorders,”“Regeneration,” “Anti-Angiogenesis Activity,” “Diseases at the CellularLevel,” and “Wound Healing and Epithelial Cell Proliferation.”(TheCaco-2 cell line is a human colorectal adenocarcinoma cell lineavailable through the ATCC as cell line number HTB-37). 197 HTEEW69Angiogenesis Highly preferred indications include diagnosis, prevention,Daudi ICAM gb|X06990|HSICAM1 treatment, and/or amelioration of diseasesand disorders Vegf1 gb|AF024710|AF024710 involving angiogenesis, woundhealing, neoplasia (particularly including, but not limited to, tumormetastases), and cardiovascular diseases and disorders; as describedherein under the headings “Hyperproliferative Disorders,”“Regeneration,” “Anti-Angiogenesis Activity,” “Diseases at the CellularLevel,” and “Wound Healing and Epithelial Cell Proliferation.”(The Daudicell line is a human B lymphoblast cell line available through the ATCCas cell line number CCL-213). 197 HTEEW69 Angiogenesis Highly preferredindications include diagnosis, prevention, HEK293 Flt1gb|AF063657|AF063657 treatment, and/or amelioration of diseases anddisorders TSP-1 gb|X04665|HSTHROMR involving angiogenesis, woundhealing, neoplasia (particularly including, but not limited to, tumormetastases), and cardiovascular diseases and disorders; as describedherein under the headings “Hyperproliferative Disorders,”“Regeneration,” “Anti-Angiogenesis Activity,” “Diseases at the CellularLevel,” and “Wound Healing and Epithelial Cell Proliferation.”(TheHEK293 cell line is a human embryonal kidney epithelial cell lineavailable through the ATCC as cell line number CRL-1573). 197 HTEEW69Angiogenesis Highly preferred indications include diagnosis, prevention,Liver ICAM gb|X06990|HSICAM1 treatment, and/or amelioration of diseasesand disorders TSP-1 gb|X04665|HSTHROMR involving angiogenesis, woundhealing, neoplasia (particularly Vegf1 gb|AF024710|AF024710 including,but not limited to, tumor metastases), and cardiovascular diseases anddisorders; as described herein under the headings “HyperproliferativeDisorders,” “Regeneration,” “Anti-Angiogenesis Activity,” “Diseases atthe Cellular Level,” and “Wound Healing and Epithelial CellProliferation.” 197 HTEEW69 Angiogenesis Highly preferred indicationsinclude diagnosis, prevention, SK-N-MC Cycloox gb|A30922|A30922treatment, and/or amelioration of diseases and disorders neuro- VCAMinvolving angiogenesis, wound healing, neoplasia (particularly blastomaincluding, but not limited to, tumor metastases), and cardiovasculardiseases and disorders; as described herein under the headings“Hyperproliferative Disorders,” “Regeneration,” “Anti-AngiogenesisActivity,” “Diseases at the Cellular Level,” and “Wound Healing andEpithelial Cell Proliferation.”(The SK-N-MC neuroblastoma cell line is acell line derived from human brain tissue available through the ATCC ascell line number HTB-10). 197 HTEEW69 Angiogenesis Highly preferredindications include diagnosis, prevention, THP1 TSP-1 gb|X04665|HSTHROMRtreatment, and/or amelioration of diseases and disorders involvingangiogenesis, wound healing, neoplasia (particularly including, but notlimited to, tumor metastases), and cardiovascular diseases anddisorders; as described herein under the headings “HyperproliferativeDisorders,” “Regeneration,” “Anti-Angiogenesis Activity,” “Diseases atthe Cellular Level,” and “Wound Healing and Epithelial CellProliferation.”(The THP-1 cell line is a human monocyte cell lineavailable through the ATCC as cell line number TIB- 202). 197 HTEEW69Angiogenesis Highly preferred indications include diagnosis, prevention,U937 Vegf1 gb|AF024710|AF024710 treatment, and/or amelioration ofdiseases and disorders involving angiogenesis, wound healing, neoplasia(particularly including, but not limited to, tumor metastases), andcardiovascular diseases and disorders; as described herein under theheadings “Hyperproliferative Disorders,” “Regeneration,”“Anti-Angiogenesis Activity,” “Diseases at the Cellular Level,” and“Wound Healing and Epithelial Cell Proliferation.”(The U937 cell line isa human monocyte cell line available through the ATCC as cell linenumber CRL- 1593.2). 40 HCEGG08 Angiogenesis Highly preferredindications include diagnosis, prevention, Caco-2 Flt1gb|AF063657|AF063657 treatment, and/or amelioration of diseases anddisorders involving angiogenesis, wound healing, neoplasia (particularlyincluding, but not limited to, tumor metastases), and cardiovasculardiseases and disorders; as described herein under the headings“Hyperproliferative Disorders,” “Regeneration,” “Anti-AngiogenesisActivity,” “Diseases at the Cellular Level,” and “Wound Healing andEpithelial Cell Proliferation.”(The Caco-2 cell line is a humancolorectal adenocarcinoma cell line available through the ATCC as cellline number HTB-37). 40 HCEGG08 Angiogenesis Highly preferredindications include diagnosis, prevention, HEK293 ICAM gb|X06990|HSICAM1treatment, and/or amelioration of diseases and disorders involvingangiogenesis, wound healing, neoplasia (particularly including, but notlimited to, tumor metastases), and cardiovascular diseases anddisorders; as described herein under the headings “HyperproliferativeDisorders,” “Regeneration,” “Anti-Angiogenesis Activity,” “Diseases atthe Cellular Level,” and “Wound Healing and Epithelial CellProliferation.”(The HEK293 cell line is a human embryonal kidneyepithelial cell line available through the ATCC as cell line numberCRL-1573). 40 HCEGG08 Angiogenesis Highly preferred indications includediagnosis, prevention, HUVEC PAI gb|X12701|HSENDPAI treatment, and/oramelioration of diseases and disorders involving angiogenesis, woundhealing, neoplasia (particularly including, but not limited to, tumormetastases), and cardiovascular diseases and disorders; as describedherein under the headings “Hyperproliferative Disorders,”“Regeneration,” “Anti-Angiogenesis Activity,” “Diseases at the CellularLevel,” and “Wound Healing and Epithelial Cell Proliferation.”(HUVECcells are human umbilical vein endothelial cells). 40 HCEGG08Angiogenesis Highly preferred indications include diagnosis, prevention,Liver ICAM gb|X06990|HSICAM1 treatment, and/or amelioration of diseasesand disorders involving angiogenesis, wound healing, neoplasia(particularly including, but not limited to, tumor metastases), andcardiovascular diseases and disorders; as described herein under theheadings “Hyperproliferative Disorders,” “Regeneration,”“Anti-Angiogenesis Activity,” “Diseases at the Cellular Level,” and“Wound Healing and Epithelial Cell Proliferation.” 40 HCEGG08Angiogenesis Highly preferred indications include diagnosis, prevention,NHDF TSP-1 gb|X04665|HSTHROMR treatment, and/or amelioration of diseasesand disorders Vegf1 gb|AF024710|AF024710 involving angiogenesis, woundhealing, neoplasia (particularly including, but not limited to, tumormetastases), and cardiovascular diseases and disorders; as describedherein under the headings “Hyperproliferative Disorders,”“Regeneration,” “Anti-Angiogenesis Activity,” “Diseases at the CellularLevel,” and “Wound Healing and Epithelial Cell Proliferation.”(NHDFcells are normal human dermal fibroblasts). 40 HCEGG08 AngiogenesisHighly preferred indications include diagnosis, prevention, SK-N-MCTSP-1 gb|X04665|HSTHROMR treatment, and/or amelioration of diseases anddisorders neuro- VCAM gb|A30922|A30922 involving angiogenesis, woundhealing, neoplasia (particularly blastoma Vegf1 gb|AF024710|AF024710including, but not limited to, tumor metastases), and cardiovasculardiseases and disorders; as described herein under the headings“Hyperproliferative Disorders,” “Regeneration,” “Anti-AngiogenesisActivity,” “Diseases at the Cellular Level,” and “Wound Healing andEpithelial Cell Proliferation.”(The SK-N-MC neuroblastoma cell line is acell line derived from human brain tissue available through the ATCC ascell line number HTB-10). 40 HCEGG08 Angiogenesis Highly preferredindications include diagnosis, prevention, THP1 VCAM gb|A30922|A30922treatment, and/or amelioration of diseases and disorders Vegf1gb|AF024710|AF024710 involving angiogenesis, wound healing, neoplasia(particularly including, but not limited to, tumor metastases), andcardiovascular diseases and disorders; as described herein under theheadings “Hyperproliferative Disorders,” “Regeneration,”“Anti-Angiogenesis Activity,” “Diseases at the Cellular Level,” and“Wound Healing and Epithelial Cell Proliferation.”(The THP-1 cell lineis a human monocyte cell line available through the ATCC as cell linenumber TIB- 202). 197 HTEEW69 Angiogenesis Highly preferred indicationsinclude diagnosis, prevention, Caco-2 iNOS gb|X85761|HSNOS2E3 treatment,and/or amelioration of diseases and disorders involving angiogenesis,wound healing, neoplasia (particularly including, but not limited to,tumor metastases), and cardiovascular diseases and disorders; asdescribed herein under the headings “Hyperproliferative Disorders,”“Regeneration,” “Anti-Angiogenesis Activity,” “Diseases at the CellularLevel,” and “Wound Healing and Epithelial Cell Proliferation.”(TheCaco-2 cell line is a human colorectal adenocarcinoma cell lineavailable through the ATCC as cell line number HTB-37). 197 HTEEW69Angiogenesis Highly preferred indications include diagnosis, prevention,Daudi ICAM gb|X06990|HSICAM1 treatment, and/or amelioration of diseasesand disorders Vegf1 gb|AF024710|AF024710 involving angiogenesis, woundhealing, neoplasia (particularly including, but not limited to, tumormetastases), and cardiovascular diseases and disorders; as describedherein under the headings “Hyperproliferative Disorders,”“Regeneration,” “Anti-Angiogenesis Activity,” “Diseases at the CellularLevel,” and “Wound Healing and Epithelial Cell Proliferation.”(The Daudicell line is a human B lymphoblast cell line available through the ATCCas cell line number CCL-213). 197 HTEEW69 Angiogenesis Highly preferredindications include diagnosis, prevention, HEK293 Flt1gb|AF063657|AF063657 treatment, and/or amelioration of diseases anddisorders TSP-1 gb|X04665|HSTHROMR involving angiogenesis, woundhealing, neoplasia (particularly including, but not limited to, tumormetastases), and cardiovascular diseases and disorders; as describedherein under the headings “Hyperproliferative Disorders,”“Regeneration,” “Anti-Angiogenesis Activity,” “Diseases at the CellularLevel,” and “Wound Healing and Epithelial Cell Proliferation.”(TheHEK293 cell line is a human embryonal kidney epithelial cell lineavailable through the ATCC as cell line number CRL-1573). 197 HTEEW69Angiogenesis Highly preferred indications include diagnosis, prevention,Liver ICAM gb|X06990|HSICAM1 treatment, and/or amelioration of diseasesand disorders TSP-1 gb|X04665|HSTHROMR involving angiogenesis, woundhealing, neoplasia (particularly Vegf1 gb|AF024710|AF024710 including,but not limited to, tumor metastases), and cardiovascular diseases anddisorders; as described herein under the headings “HyperproliferativeDisorders,” “Regeneration,” “Anti-Angiogenesis Activity,” “Diseases atthe Cellular Level,” and “Wound Healing and Epithelial CellProliferation.” 197 HTEEW69 Angiogenesis Highly preferred indicationsinclude diagnosis, prevention, SK-N-MC Cycloox gb|A30922|A30922treatment, and/or amelioration of diseases and disorders neuro- VCAMinvolving angiogenesis, wound healing, neoplasia (particularly blastomaincluding, but not limited to, tumor metastases), and cardiovasculardiseases and disorders; as described herein under the headings“Hyperproliferative Disorders,” “Regeneration,” “Anti-AngiogenesisActivity,” “Diseases at the Cellular Level,” and “Wound Healing andEpithelial Cell Proliferation.”(The SK-N-MC neuroblastoma cell line is acell line derived from human brain tissue available through the ATCC ascell line number HTB-10). 197 HTEEW69 Angiogenesis Highly preferredindications include diagnosis, prevention, THP1 TSP-1 gb|X04665|HSTHROMRtreatment, and/or amelioration of diseases and disorders involvingangiogenesis, wound healing, neoplasia (particularly including, but notlimited to, tumor metastases), and cardiovascular diseases anddisorders; as described herein under the headings “HyperproliferativeDisorders,” “Regeneration,” “Anti-Angiogenesis Activity,” “Diseases atthe Cellular Level,” and “Wound Healing and Epithelial CellProliferation.”(The THP-1 cell line is a human monocyte cell lineavailable through the ATCC as cell line number TIB- 202). 197 HTEEW69Angiogenesis Highly preferred indications include diagnosis, prevention,U937 Vegf1 gb|AF024710|AF024710 treatment, and/or amelioration ofdiseases and disorders involving angiogenesis, wound healing, neoplasia(particularly including, but not limited to, tumor metastases), andcardiovascular diseases and disorders; as described herein under theheadings “Hyperproliferative Disorders,” “Regeneration,”“Anti-Angiogenesis Activity,” “Diseases at the Cellular Level,” and“Wound Healing and Epithelial Cell Proliferation.”(The U937 cell line isa human monocyte cell line available through the ATCC as cell linenumber CRL- 1593.2). 40 HCEGG08 Angiogenesis Highly preferredindications include diagnosis, prevention, Caco-2 Flt1gb|AF063657|AF063657 treatment, and/or amelioration of diseases anddisorders involving angiogenesis, wound healing, neoplasia (particularlyincluding, but not limited to, tumor metastases), and cardiovasculardiseases and disorders; as described herein under the headings“Hyperproliferative Disorders,” “Regeneration,” “Anti-AngiogenesisActivity,” “Diseases at the Cellular Level,” and “Wound Healing andEpithelial Cell Proliferation.”(The Caco-2 cell line is a humancolorectal adenocarcinoma cell line available through the ATCC as cellline number HTB-37). 40 HCEGG08 Angiogenesis Highly preferredindications include diagnosis, prevention, HEK293 ICAM gb|X06990|HSICAM1treatment, and/or amelioration of diseases and disorders involvingangiogenesis, wound healing, neoplasia (particularly including, but notlimited to, tumor metastases), and cardiovascular diseases anddisorders; as described herein under the headings “HyperproliferativeDisorders,” “Regeneration,” “Anti-Angiogenesis Activity,” “Diseases atthe Cellular Level,” and “Wound Healing and Epithelial CellProliferation.”(The HEK293 cell line is a human embryonal kidneyepithelial cell line available through the ATCC as cell line numberCRL-1573). 40 HCEGG08 Angiogenesis Highly preferred indications includediagnosis, prevention, HUVEC PAI gb|X12701|HSENDPAI treatment, and/oramelioration of diseases and disorders involving angiogenesis, woundhealing, neoplasia (particularly including, but not limited to, tumormetastases), and cardiovascular diseases and disorders; as describedherein under the headings “Hyperproliferative Disorders,”“Regeneration,” “Anti-Angiogenesis Activity,” “Diseases at the CellularLevel,” and “Wound Healing and Epithelial Cell Proliferation.”(HUVECcells are human umbilical vein endothelial cells). 40 HCEGG08Angiogenesis Highly preferred indications include diagnosis, prevention,Liver ICAM gb|X06990|HSICAM1 treatment, and/or amelioration of diseasesand disorders involving angiogenesis, wound healing, neoplasia(particularly including, but not limited to, tumor metastases), andcardiovascular diseases and disorders; as described herein under theheadings “Hyperproliferative Disorders,” “Regeneration,”“Anti-Angiogenesis Activity,” “Diseases at the Cellular Level,” and“Wound Healing and Epithelial Cell Proliferation.” 40 HCEGG08Angiogenesis Highly preferred indications include diagnosis, prevention,NHDF TSP-1 gb|X04665|HSTHROMR treatment, and/or amelioration of diseasesand disorders Vegf1 gb|AF024710|AF024710 involving angiogenesis, woundhealing, neoplasia (particularly including, but not limited to, tumormetastases), and cardiovascular diseases and disorders; as describedherein under the headings “Hyperproliferative Disorders,”“Regeneration,” “Anti-Angiogenesis Activity,” “Diseases at the CellularLevel,” and “Wound Healing and Epithelial Cell Proliferation.”(NHDFcells are normal human dermal fibroblasts). 40 HCEGG08 AngiogenesisHighly preferred indications include diagnosis, prevention, SK-N-MCTSP-1 gb|X04665|HSTHROMR treatment, and/or amelioration of diseases anddisorders neuro- VCAM gb|A30922|A30922 involving angiogenesis, woundhealing, neoplasia (particularly blastoma Vegf1 gb|AF024710|AF024710including, but not limited to, tumor metastases), and cardiovasculardiseases and disorders; as described herein under the headings“Hyperproliferative Disorders,” “Regeneration,” “Anti-AngiogenesisActivity,” “Diseases at the Cellular Level,” and “Wound Healing andEpithelial Cell Proliferation.”(The SK-N-MC neuroblastoma cell line is acell line derived from human brain tissue available through the ATCC ascell line number HTB-10). 40 HCEGG08 Angiogenesis Highly preferredindications include diagnosis, prevention, THP1 VCAM gb|A30922|A30922treatment, and/or amelioration of diseases and disorders Vegf1gb|AF024710|AF024710 involving angiogenesis, wound healing, neoplasia(particularly including, but not limited to, tumor metastases), andcardiovascular diseases and disorders; as described herein under theheadings “Hyperproliferative Disorders,” “Regeneration,”“Anti-Angiogenesis Activity,” “Diseases at the Cellular Level,” and“Wound Healing and Epithelial Cell Proliferation.”(The THP-1 cell lineis a human monocyte cell line available through the ATCC as cell linenumber TIB- 202). 197 HTEEW69 Angiogenesis Highly preferred indicationsinclude diagnosis, prevention, Caco-2 iNOS gb|X85761|HSNOS2E3 treatment,and/or amelioration of diseases and disorders involving angiogenesis,wound healing, neoplasia (particularly including, but not limited to,tumor metastases), and cardiovascular diseases and disorders; asdescribed herein under the headings “Hyperproliferative Disorders,”“Regeneration,” “Anti-Angiogenesis Activity,” “Diseases at the CellularLevel,” and “Wound Healing and Epithelial Cell Proliferation.”(TheCaco-2 cell line is a human colorectal adenocarcinoma cell lineavailable through the ATCC as cell line number HTB-37). 197 HTEEW69Angiogenesis Highly preferred indications include diagnosis, prevention,Daudi ICAM gb|X06990|HSICAM1 treatment, and/or amelioration of diseasesand disorders Vegf1 gb|AF024710|AF024710 involving angiogenesis, woundhealing, neoplasia (particularly including, but not limited to, tumormetastases), and cardiovascular diseases and disorders; as describedherein under the headings “Hyperproliferative Disorders,”“Regeneration,” “Anti-Angiogenesis Activity,” “Diseases at the CellularLevel,” and “Wound Healing and Epithelial Cell Proliferation.”(The Daudicell line is a human B lymphoblast cell line available through the ATCCas cell line number CCL-213). 197 HTEEW69 Angiogenesis Highly preferredindications include diagnosis, prevention, HEK293 Flt1gb|AF063657|AF063657 treatment, and/or amelioration of diseases anddisorders TSP-1 gb|X04665|HSTHROMR involving angiogenesis, woundhealing, neoplasia (particularly including, but not limited to, tumormetastases), and cardiovascular diseases and disorders; as describedherein under the headings “Hyperproliferative Disorders,”“Regeneration,” “Anti-Angiogenesis Activity,” “Diseases at the CellularLevel,” and “Wound Healing and Epithelial Cell Proliferation.”(TheHEK293 cell line is a human embryonal kidney epithelial cell lineavailable through the ATCC as cell line number CRL-1573). 197 HTEEW69Angiogenesis Highly preferred indications include diagnosis, prevention,Liver ICAM gb|X06990|HSICAM1 treatment, and/or amelioration of diseasesand disorders TSP-1 gb|X04665|HSTHROMR involving angiogenesis, woundhealing, neoplasia (particularly Vegf1 gb|AF024710|AF024710 including,but not limited to, tumor metastases), and cardiovascular diseases anddisorders; as described herein under the headings “HyperproliferativeDisorders,” “Regeneration,” “Anti-Angiogenesis Activity,” “Diseases atthe Cellular Level,” and “Wound Healing and Epithelial CellProliferation.” 197 HTEEW69 Angiogenesis Highly preferred indicationsinclude diagnosis, prevention, SK-N-MC Cycloox gb|A30922|A30922treatment, and/or amelioration of diseases and disorders neuro- VCAMinvolving angiogenesis, wound healing, neoplasia (particularly blastomaincluding, but not limited to, tumor metastases), and cardiovasculardiseases and disorders; as described herein under the headings“Hyperproliferative Disorders,” “Regeneration,” “Anti-AngiogenesisActivity,” “Diseases at the Cellular Level,” and “Wound Healing andEpithelial Cell Proliferation.”(The SK-N-MC neuroblastoma cell line is acell line derived from human brain tissue available through the ATCC ascell line number HTB-10). 197 HTEEW69 Angiogenesis Highly preferredindications include diagnosis, prevention, THP1 TSP-1 gb|X04665|HSTHROMRtreatment, and/or amelioration of diseases and disorders involvingangiogenesis, wound healing, neoplasia (particularly including, but notlimited to, tumor metastases), and cardiovascular diseases anddisorders; as described herein under the headings “HyperproliferativeDisorders,” “Regeneration,” “Anti-Angiogenesis Activity,” “Diseases atthe Cellular Level,” and “Wound Healing and Epithelial CellProliferation.”(The THP-1 cell line is a human monocyte cell lineavailable through the ATCC as cell line number TIB- 202). 197 HTEEW69Angiogenesis Highly preferred indications include diagnosis, prevention,U937 Vegf1 gb|AF024710|AF024710 treatment, and/or amelioration ofdiseases and disorders involving angiogenesis, wound healing, neoplasia(particularly including, but not limited to, tumor metastases), andcardiovascular diseases and disorders; as described herein under theheadings “Hyperproliferative Disorders,” “Regeneration,”“Anti-Angiogenesis Activity,” “Diseases at the Cellular Level,” and“Wound Healing and Epithelial Cell Proliferation.”(The U937 cell line isa human monocyte cell line available through the ATCC as cell linenumber CRL- 1593.2). 40 HCEGG08 Angiogenesis Highly preferredindications include diagnosis, prevention, Caco-2 Flt1gb|AF063657|AF063657 treatment, and/or amelioration of diseases anddisorders involving angiogenesis, wound healing, neoplasia (particularlyincluding, but not limited to, tumor metastases), and cardiovasculardiseases and disorders; as described herein under the headings“Hyperproliferative Disorders,” “Regeneration,” “Anti-AngiogenesisActivity,” “Diseases at the Cellular Level,” and “Wound Healing andEpithelial Cell Proliferation.”(The Caco-2 cell line is a humancolorectal adenocarcinoma cell line available through the ATCC as cellline number HTB-37). 40 HCEGG08 Angiogenesis Highly preferredindications include diagnosis, prevention, HEK293 ICAM gb|X06990|HSICAM1treatment, and/or amelioration of diseases and disorders involvingangiogenesis, wound healing, neoplasia (particularly including, but notlimited to, tumor metastases), and cardiovascular diseases anddisorders; as described herein under the headings “HyperproliferativeDisorders,” “Regeneration,” “Anti-Angiogenesis Activity,” “Diseases atthe Cellular Level,” and “Wound Healing and Epithelial CellProliferation.”(The HEK293 cell line is a human embryonal kidneyepithelial cell line available through the ATCC as cell line numberCRL-1573). 40 HCEGG08 Angiogenesis Highly preferred indications includediagnosis, prevention, HUVEC PAI gb|X12701|HSENDPAI treatment, and/oramelioration of diseases and disorders involving angiogenesis, woundhealing, neoplasia (particularly including, but not limited to, tumormetastases), and cardiovascular diseases and disorders; as describedherein under the headings “Hyperproliferative Disorders,”“Regeneration,” “Anti-Angiogenesis Activity,” “Diseases at the CellularLevel,” and “Wound Healing and Epithelial Cell Proliferation.”(HUVECcells are human umbilical vein endothelial cells). 40 HCEGG08Angiogenesis Highly preferred indications include diagnosis, prevention,Liver ICAM gb|X06990|HSICAM1 treatment, and/or amelioration of diseasesand disorders involving angiogenesis, wound healing, neoplasia(particularly including, but not limited to, tumor metastases), andcardiovascular diseases and disorders; as described herein under theheadings “Hyperproliferative Disorders,” “Regeneration,”“Anti-Angiogenesis Activity,” “Diseases at the Cellular Level,” and“Wound Healing and Epithelial Cell Proliferation.” 40 HCEGG08Angiogenesis Highly preferred indications include diagnosis, prevention,NHDF TSP-1 gb|X04665|HSTHROMR treatment, and/or amelioration of diseasesand disorders Vegf1 gb|AF024710|AF024710 involving angiogenesis, woundhealing, neoplasia (particularly including, but not limited to, tumormetastases), and cardiovascular diseases and disorders; as describedherein under the headings “Hyperproliferative Disorders,”“Regeneration,” “Anti-Angiogenesis Activity,” “Diseases at the CellularLevel,” and “Wound Healing and Epithelial Cell Proliferation.”(NHDFcells are normal human dermal fibroblasts). 40 HCEGG08 AngiogenesisHighly preferred indications include diagnosis, prevention, SK-N-MCTSP-1 gb|X04665|HSTHROMR treatment, and/or amelioration of diseases anddisorders neuro- VCAM gb|A30922|A30922 involving angiogenesis, woundhealing, neoplasia (particularly blastoma Vegf1 gb|AF024710|AF024710including, but not limited to, tumor metastases), and cardiovasculardiseases and disorders; as described herein under the headings“Hyperproliferative Disorders,” “Regeneration,” “Anti-AngiogenesisActivity,” “Diseases at the Cellular Level,” and “Wound Healing andEpithelial Cell Proliferation.”(The SK-N-MC neuroblastoma cell line is acell line derived from human brain tissue available through the ATCC ascell line number HTB-10). 40 HCEGG08 Angiogenesis Highly preferredindications include diagnosis, prevention, THP1 VCAM gb|A30922|A30922treatment, and/or amelioration of diseases and disorders Vegf1gb|AF024710|AF024710 involving angiogenesis, wound healing, neoplasia(particularly including, but not limited to, tumor metastases), andcardiovascular diseases and disorders; as described herein under theheadings “Hyperproliferative Disorders,” “Regeneration,”“Anti-Angiogenesis Activity,” “Diseases at the Cellular Level,” and“Wound Healing and Epithelial Cell Proliferation.”(The THP-1 cell lineis a human monocyte cell line available through the ATCC as cell linenumber TIB- 202). 197 HTEEW69 Angiogenesis Highly preferred indicationsinclude diagnosis, prevention, Caco-2 iNOS gb|X85761|HSNOS2E3 treatment,and/or amelioration of diseases and disorders involving angiogenesis,wound healing, neoplasia (particularly including, but not limited to,tumor metastases), and cardiovascular diseases and disorders; asdescribed herein under the headings “Hyperproliferative Disorders,”“Regeneration,” “Anti-Angiogenesis Activity,” “Diseases at the CellularLevel,” and “Wound Healing and Epithelial Cell Proliferation.”(TheCaco-2 cell line is a human colorectal adenocarcinoma cell lineavailable through the ATCC as cell line number HTB-37). 197 HTEEW69Angiogenesis Highly preferred indications include diagnosis, prevention,Daudi ICAM gb|X06990|HSICAM1 treatment, and/or amelioration of diseasesand disorders Vegf1 gb|AF024710|AF024710 involving angiogenesis, woundhealing, neoplasia (particularly including, but not limited to, tumormetastases), and cardiovascular diseases and disorders; as describedherein under the headings “Hyperproliferative Disorders,”“Regeneration,” “Anti-Angiogenesis Activity,” “Diseases at the CellularLevel,” and “Wound Healing and Epithelial Cell Proliferation.”(The Daudicell line is a human B lymphoblast cell line available through the ATCCas cell line number CCL-213). 197 HTEEW69 Angiogenesis Highly preferredindications include diagnosis, prevention, HEK293 Flt1gb|AF063657|AF063657 treatment, and/or amelioration of diseases anddisorders TSP-1 gb|X04665|HSTHROMR involving angiogenesis, woundhealing, neoplasia (particularly including, but not limited to, tumormetastases), and cardiovascular diseases and disorders; as describedherein under the headings “Hyperproliferative Disorders,”“Regeneration,” “Anti-Angiogenesis Activity,” “Diseases at the CellularLevel,” and “Wound Healing and Epithelial Cell Proliferation.”(TheHEK293 cell line is a human embryonal kidney epithelial cell lineavailable through the ATCC as cell line number CRL-1573).

Table 2 further characterizes certain encoded polypeptides of theinvention, by providing the results of comparisons to protein andprotein family databases. The first column provides a unique cloneidentifier, “Clone ID NO:”, corresponding to a cDNA clone disclosed inTable 1A and/or Table 1B. The second column provides the unique contigidentifier, “Contig ID:” which allows correlation with the informationin Table 1B. The third column provides the sequence identifier, “SEQ IDNO:”, for the contig polynucleotide sequences. The fourth columnprovides the analysis method by which the homology/identity disclosed inthe Table was determined. The fifth column provides a description of thePFAM/NR hit identified by each analysis. Column six provides theaccession number of the PFAM/NR hit disclosed in the fifth column.Column seven, score/percent identity, provides a quality score or thepercent identity, of the hit disclosed in column five. Comparisons weremade between polypeptides encoded by polynucleotides of the inventionand a non-redundant protein database (herein referred to as “NR”), or adatabase of protein families (herein referred to as “PFAM”), asdescribed below.

The NR database, which comprises the NBRF PIR database, the NCBI GenPeptdatabase, and the SIB SwissProt and TrEMBL databases, was madenon-redundant using the computer program nrdb2 (Warren Gish, WashingtonUniversity in Saint Louis). Each of the polynucleotides shown in Table1B (e.g., SEQ ID NO:X or the ‘Query’ sequence) was used to searchagainst the NR database. The computer program BLASTX was used to comparea 6-frame translation of the Query sequence to the NR database (forinformation about the BLASTX algorithm please see Altshul et al., J.Mol. Biol. 215:403410 (1990), and Gish and States, Nat. Genet. 3:266-272(1993). A description of the sequence that is most similar to the Querysequence (the highest scoring ‘Subject’) is shown in column five ofTable 2 and the database accession number for that sequence is providedin column six. The highest scoring ‘Subject’ is reported in Table 2 if(a) the estimated probability that the match occurred by chance alone isless than 1.0e-07, and (b) the match was not to a known repetitiveelement. BLASTX returns alignments of short polypeptide segments of theQuery and Subject sequences which share a high degree of similarity;these segments are known as High-Scoring Segment Pairs or HSPs. Table 2reports the degree of similarity between the Query and the Subject foreach HSP as a percent identity in Column 7. The percent identity isdetermined by dividing the number of exact matches between the twoaligned sequences in the HSP, dividing by the number of Query aminoacids in the HSP and multiplying by 100. The polynucleotides of SEQ IDNO:X which encode the polypeptide sequence that generates an HSP aredelineated by columns 8 and 9 of Table 2.

The PFAM database, PFAM version 2.1, (Sonnhammer, Nucl. Acids Res.,26:320-322, 1998)) consists of a series of multiple sequence alignments;one alignment for each protein family. Each multiple sequence alignmentis converted into a probability model called a Hidden Markov Model, orHMM, that represents the position-specific variation among the sequencesthat make up the multiple sequence alignment (see, e.g., Durbin, et al.,Biological sequence analysis: probabilistic models of proteins andnucleic acids, Cambridge University Press, 1998 for the theory of HMMs).The program HMMER version 1.8 (Sean Eddy, Washington University in SaintLouis) was used to compare the predicted protein sequence for each Querysequence (SEQ ID NO:Y in Table 1B) to each of the HMMs derived from PFAMversion 2.1. A HMM derived from PFAM version 2.1 was said to be asignificant match to a polypeptide of the invention if the scorereturned by HMMER 1.8 was greater than 0.8 times the HMMER 1.8 scoreobtained with the most distantly related known member of that proteinfamily. The description of the PFAM family which shares a significantmatch with a polypeptide of the invention is listed in column 5 of Table2, and the database accession number of the PFAM hit is provided incolumn 6. Column 7 provides the score returned by HMMER version 1.8 forthe alignment. Columns 8 and 9 delineate the polynucleotides of SEQ IDNO:X which encode the polypeptide sequence which show a significantmatch to a PFAM protein family.

As mentioned, columns 8 and 9 in Table 2, “NT From” and “NT To”,delineate the polynucleotides of “SEQ ID NO:X” that encode a polypeptidehaving a significant match to the PFAM/NR database as disclosed in thefifth column. In one embodiment, the invention provides a proteincomprising, or alternatively consisting of, a polypeptide encoded by thepolynucleotides of SEQ ID NO:X delineated in columns 8 and 9 of Table 2.Also provided are polynucleotides encoding such proteins, and thecomplementary strand thereto.

The nucleotide sequence SEQ ID NO:X and the translated SEQ ID NO:Y aresufficiently accurate and otherwise suitable for a variety of uses wellknown in the art and described further below. For instance, thenucleotide sequences of SEQ ID NO:X are useful for designing nucleicacid hybridization probes that will detect nucleic acid sequencescontained in SEQ ID NO:X or the cDNA contained in ATCC Deposit No:Z.These probes will also hybridize to nucleic acid molecules in biologicalsamples, thereby enabling immediate applications in chromosome mapping,linkage analysis, tissue identification and/or typing, and a variety offorensic and diagnostic methods of the invention. Similarly,polypeptides identified from SEQ ID NO:Y may be used to generateantibodies which bind specifically to these polypeptides, or fragmentsthereof, and/or to the polypeptides encoded by the cDNA clonesidentified in, for example, Table 1A and/or 1B.

Nevertheless, DNA sequences generated by sequencing reactions cancontain sequencing errors. The errors exist as misidentifiednucleotides, or as insertions or deletions of nucleotides in thegenerated DNA sequence. The erroneously inserted or deleted nucleotidescause frame shifts in the reading frames of the predicted amino acidsequence. In these cases, the predicted amino acid sequence divergesfrom the actual amino acid sequence, even though the generated DNAsequence may be greater than 99.9% identical to the actual DNA sequence(for example, one base insertion or deletion in an open reading frame ofover 1000 bases).

Accordingly, for those applications requiring precision in thenucleotide sequence or the amino acid sequence, the present inventionprovides not only the generated nucleotide sequence identified as SEQ IDNO:X, and a predicted translated amino acid sequence identified as SEQID NO:Y, but also a sample of plasmid DNA containing cDNA ATCC DepositNo:Z (e.g., as set forth in columns 2 and 3 of Table 1A and/or as setforth, for example, in Table 1B, 6, and 7). The nucleotide sequence ofeach deposited clone can readily be determined by sequencing thedeposited clone in accordance with known methods. Further, techniquesknown in the art can be used to verify the nucleotide sequences of SEQID NO:X. The predicted amino acid sequence can then be verified fromsuch deposits. Moreover, the amino acid sequence of the protein encodedby a particular clone can also be directly determined by peptidesequencing or by expressing the protein in a suitable host cellcontaining the deposited human cDNA, collecting the protein, anddetermining its sequence. TABLE 2 Score/ cDNA SEQ ID Analysis PFam/NRPercent NT Clone ID Contig ID: NO: X Method PFam/NR DescriptionAccession Number Identity From NT To H6BSF56 762968 11 HMMER PFAM:Zinc-binding dehydrogenases PF00107 35.6 176 415 2.1.1 WUblastx.64(Q9BV79) SIMILAR TO CGI-63 PROTEIN. Q9BV79 100% 25 42 92% 53 427 H6EDM64841331 12 WUblastx.64 (Q9UID3) ANG2. Q9UID3 90% 928 2451 36% 203 310 36%931 1038 95% 191 871 H6EEC72 889401 13 WUblastx.64 hypothetical proteinDKFZp434L061.1 - human pir|T43456|T43456 80% 1484 1203 41% 1277 1080 35%973 845 34% 659 549 57% 991 365 HACBJ56 847112 16 WUblastx.64 (Q9D2Q2)2310079F23RIK PROTEIN. Q9D2Q2 65% 98 286 HADMB15 847116 17 WUblastx.64(Q9BVH1) SIMILAR TO DLXIN-1. Q9BVH1 100% 8 109 HAGFS57 847120 18WUblastx.64 (Q9Y485) X-LIKE 1 PROTEIN. Q9Y485 58% 9 872 HAGHN57 77328619 WUblastx.64 (O60416) WUGSC: H_RG276O03.2 PROTEIN. O60416 98% 65 1444HAJAA47 534670 20 WUblastx.64 (Q9NZA3) CDA14. Q9NZA3 100% 17 157 HAJAY92845601 21 WUblastx.64 (O00549) ORF2-LIKE PROTEIN O00549 53% 2226 2318(FRAGMENT). 26% 769 915 38% 1653 1769 31% 1721 2242 HAJBV67 866415 22WUblastx.64 (Q9HD45) TRANSMEMBRANE 9 T9S3_HUMAN 100% 13 126 SUPERFAMILYPROTEIN MEMBER 3 93% 116 1681 PRECU HBAGD86 838799 25 WUblastx.64(Q14287) HYPOTHETICAL PROTEIN Q14287 37% 801 559 (FRAGMENT). HBGBC29691473 26 WUblastx.64 (O60513) BETA-1,4- B4G4_HUMAN 61% 1 78GALACTOSYLTRANSFERASE 4 (EC 2.4.1.—) 98% 65 1021 (BET HBHAA05 603174 28WUblastx.64 (Q9H387) PRO2550. Q9H387 71% 676 386 HBHAA81 846465 29WUblastx.64 (Q9D1G3) 1110011D13RIK PROTEIN. Q9D1G3 89% 1329 1502 79% 281329 HBIAC29 831751 30 WUblastx.64 (Q9D7J5) 2310005N01RIK PROTEIN.Q9D7J5 78% 25 492 93% 883 927 HBJAB02 837309 31 WUblastx.64 (Q9NXT6)CDNA FLJ20062 FIS, CLONE Q9NXT6 70% 2 1210 COL01508. HBJAC40 841235 32WUblastx.64 (Q9P112) CHROMOSOME 16 OPEN Q9P112 100% 8 73 READING FRAME5. 36% 5 70 57% 11 52 53% 85 180 100% 192 632 HBJCR46 815649 33 HMMERPFAM: WD domain, G-beta repeat PF00400 36.6 790 867 2.1.1 WUblastx.64(Q9DC22) 1200006M05RIK PROTEIN. Q9DC22 96% 207 611 73% 568 2763 HBJEL16847030 35 WUblastx.64 (O95297) PROTEIN ZERO RELATED O95297 98% 285 491PROTEIN. HBJKD16 853358 36 WUblastx.64 (Q9NXS4) CDNA FLJ20080 FIS, CLONEQ9NXS4 91% 8 1528 COL03184. HBMBM96 561935 37 WUblastx.64 (Q9H387)PRO2550. Q9H387 69% 661 494 67% 794 639 HBMUH74 866160 39 WUblastx.64(Q9NVW8) CDNA FLJ10462 FIS, CLONE Q9NVW8 100% 11 427 NT2RP1001494,WEAKLY SIMILAR TO MAL HBQAB79 810542 40 WUblastx.64 (Q9UQ32) AD 3(FRAGMENT). Q9UQ32 82% 323 204 HBSAK32 856387 41 WUblastx.64 (Q9H1Q7)BA12M19.1.3 (NOVEL PROTEIN). Q9H1Q7 100% 239 412 100% 95 172 HBXCX15637542 42 WUblastx.64 (Q9GMX5) HYPOTHETICAL 12.9 KDA Q9GMX5 41% 726 827PROTEIN. 52% 578 730 HCDCY76 837972 43 WUblastx.64 frizzled protein 4 -human pir|JC7127|JC7127 100% 1039 527 30% 994 785 79% 567 37 HCE1G78761204 45 HMMER PFAM: Inositol polyphosphate phosphatase PF00783 277.377 775 2.1.1 family, catalytic domain WUblastx.64 (Q9UDT9) WUGSC:H_DJ412A9.2 PROTEIN Q9UDT9 72% 8 1549 (FRAGMENT). 95% 8 67 HCEDR26771144 47 WUblastx.64 (Q9H919) CDNA FLJ13078 FIS, CLONE Q9H919 66% 11571095 NT2RP3002002. 66% 1345 1184 HCEEQ25 531784 48 WUblastx.64 (P78349)SODIUM CHANNEL 2. P78349 95% 311 433 93% 433 480 100% 658 714 HCEEU18688041 49 WUblastx.64 (Q9N083) UNNAMED PORTEIN PRODUCT. Q9N083 49% 18610 56% 1223 933 HCFLN88 610000 51 WUblastx.64 (Q9BQE9) SIMILAR TO B-CELLQ9BQE9 87% 278 475 CLL/LYMPHOMA 7B (UNKNOWN) (PROTEIN FOR MGC HCHAB84834326 52 WUblastx.64 (Q9BRV3) STROMAL CELL PROTEIN. Q9BRV3 89% 82 744HCNSD29 862314 55 WUblastx.64 (O75400) HUNTINGTIN-INTERACTING O75400 82%628 1605 PROTEIN HYPA/FBP11 (FRAGMENT). 78% 337 489 HCUCF89 637986 58WUblastx.64 (Q9P147) PRO2822. Q9P147 100% 421 398 82% 494 426 HCUCK44790277 59 WUblastx.64 hypothetical protein DKFZp564J157.1 - humanpir|T34520|T34520 100% 29 157 (fragment) 100% 377 403 HDPDI72 897277 62WUblastx.64 adult-specific brush border protein - rabbitpir|C45665|C45665 64% 180 230 83% 11 100 HDPGE24 801947 63 WUblastx.64(Q9P195) PRO1722. Q9P195 65% 1413 1291 43% 1388 1278 77% 2528 2394 47%2182 2078 75% 1774 1751 62% 2604 2557 68% 1301 1167 HDPIU94 813352 64WUblastx.64 (Q9BVF7) SIMILAR TO HYPOTHETICAL Q9BVF7 99% 63 1703 PROTEINFLJ10422. HDPIY31 886159 65 WUblastx.64 hypothetical proteinDKFZp434N1429.1 - pir|T46448|T46448 72% 1714 1899 human (fragment)HDPOC24 777493 66 WUblastx.64 (Q9H8K1) CDNA FLJ13518 FIS, CLONE Q9H8K1100% 62 208 PLACE1005799. HDPOL37 745377 67 WUblastx.64 (AAK40301) TRH4.AAK40301 70% 502 323 60% 1325 483 HDPPQ30 684292 69 WUblastx.64 (Q9H387)PRO2550. Q9H387 51% 807 727 79% 1042 815 HDQHM36 852328 70 WUblastx.64(Q9N083) UNNAMED PORTEIN PRODUCT. Q9N083 69% 1129 1257 50% 965 1153HE6FU11 827236 73 HMMER PFAM: von Willebrand factor type A domainPF00092 184.7 244 771 2.1.1 WUblastx.64 (O95460) MATRILIN-4 PRECURSOR.MTN4_HUMAN 77% 145 789 45% 782 907 41% 791 925 50% 794 907 38% 863 149833% 190 741 98% 782 1642 HE9EA10 827796 75 WUblastx.64 laminin alpha-1chain precursor - human pir|S14458|S14458 99% 761 1891 27% 878 1840 25%1142 1876 HEBFR46 847064 79 WUblastx.64 (Q9NX85) CDNA FLJ20378 FIS,CLONE Q9NX85 80% 1111 1022 KAIA0536. 84% 1265 1110 HEBGE07 798096 80WUblastx.64 (Q9NX85) CDNA FLJ20378 FIS, CLONE Q9NX85 79% 1851 1720KAIA0536. HEQBF89 786205 82 WUblastx.64 (Q9H728) CDNA: FLJ21463 FIS,CLONE Q9H728 64% 793 638 COL04765. 64% 647 489 HFEAY59 658685 84WUblastx.64 (Q9Z320) C29. Q9Z320 67% 50 1153 HFIJA68 847074 85WUblastx.64 (Q9UHE8) SIX TRANSMEMBRANE STEA_HUMAN 89% 13 399 EPITHELIALANTIGEN OF PROSTATE. HFKEU12 634006 86 WUblastx.64 hypothetical protein3 - rat pir|S21347|S21347 52% 695 745 50% 757 933 40% 774 1007 54% 387692 HFVHW43 570948 90 WUblastx.64 (Q9BGX4) HYPOTHETICAL 13.8 KDA Q9BGX469% 1209 1093 PROTEIN. HGBHP91 693011 91 WUblastx.64 hypotheticalprotein (L1H 3′ region) - human pir|B34087|B34087 52% 541 491 44% 537 34HHEAK45 765278 92 WUblastx.64 (Q9NPB0) DJ202I21.1 (NOVEL PROTEIN) Q9NPB068% 1949 1458 (CDNA FLJ11101 FIS, CLONE PLACE10 HHEOW19 886174 94WUblastx.64 (O18973) RAB5 GDP/GTP EXCHANGE O18973 77% 417 623 FACTOR,RABEX5. 91% 611 715 56% 166 378 92% 129 167 HHFFL34 753230 95WUblastx.64 (BAB55306) CDNA FLJ14793 fis, clone BAB55306 100% 9 710NT2RP4001174, w HHFFS40 824059 96 WUblastx.64 (Q9H4A6) GOLGI PROTEIN.Q9H4A6 100% 3 251 HHGDT26 658692 98 WUblastx.64 (Q9H728) CDNA: FLJ21463FIS, CLONE Q9H728 69% 1580 1290 COL04765. HHSBI65 801910 101 WUblastx.64(Q9H5W9) CDNA: FLJ22888 FIS, CLONE Q9H5W9 100% 270 407 KAT03934. 94% 4791300 HHSDI53 862028 102 WUblastx.64 (Q9H387) PRO2550. Q9H387 70% 1108935 71% 1241 1107 75% 1276 1241 HISAT67 843549 103 WUblastx.64 (Q9UH94)PROLACTIN REGULATORY Q9UH94 88% 219 797 ELEMENT-BINDING PROTEIN(PROLACTIN 91% 788 1447 REGU HJBCU75 638329 104 WUblastx.64 (O45030)STRABISMUS. O45030 44% 199 426 52% 464 964 HJMAA03 824062 105WUblastx.64 (Q9N032) UNNAMED PROTEIN PRODUCT. Q9N032 71% 415 528 HJMAV41862029 106 WUblastx.64 brain-specific membrane anchor protein - humanpir|JC7110|JC7110 100% 14 475 HJMAY90 793678 107 WUblastx.64 (Q9DC16)1200007D18RIK PROTEIN (RIKEN Q9DC16 77% 100 312 CDNA 1200007D18 GENE).98% 315 968 HJPBE39 801960 108 WUblastx.64 (Q9CUS4) 4833420K19RIKPROTEIN Q9CUS4 33% 1 621 (FRAGMENT). 74% 213 1007 HJPCH08 840365 109WUblastx.64 (O95235) RABKINESIN-6 (RAB6- RB6K_HUMAN 93% 9 596INTERACTING KINESIN-LIKE PROTEI HKGBF25 738797 110 WUblastx.64 (Q9HBS7)HYPOTHETICAL 14.2 KDA Q9HBS7 71% 1708 1688 PROTEIN. 56% 1956 1708HLDQU79 740755 114 WUblastx.64 (O75477) KE04P. O75477 100% 105 1142HLDQU79 837599 253 blastx.2 KE04P. sp|O75477|O75477 99% 81 1118 HLDRT09830544 115 WUblastx.64 (Q9HAQ7) ATP-BINDING CASSETTE HALF- Q9HAQ7 86% 2469 TRANSPORTER. HLHAP05 638476 116 WUblastx.64 (Q9HA67) CDNA FLJ12155FIS, CLONE Q9HA67 55% 1553 1500 MAMMA1000472. 72% 1650 1585 77% 18071646 HLIBO72 883431 118 WUblastx.64 (AAH07829) Similar to hypotheticalprotein AAH07829 100% 65 547 AF140225 HLICE88 840321 119 WUblastx.64fibrinogen gamma-A chain precursor [validated] - pir|A90470|FGHUG 89% 3584 human HLYGY91 658703 126 WUblastx.64 (Q9H8N0) CDNA FLJ13386 FIS,CLONE Q9H8N0 94% 221 391 PLACE1001104, WEAKLY SIMILAR TO MYO HMDAB29584789 128 WUblastx.64 (Q9NX17) CDNA FLJ20489 FIS, CLONE Q9NX17 72% 1186890 KAT08285. HMEDI90 840077 130 WUblastx.64 (Q9HBA3) RAB3 INTERACTINGPROTEIN Q9HBA3 100% 81 794 VARIANT 4 (FRAGMENT). HMTAB77 847411 135WUblastx.64 (P43243) MATRIN 3. MAT3_HUMAN 95% 630 1385 64% 287 628 22%2002 2175 98% 3255 3428 31% 2041 2190 22% 2047 2181 23% 2584 2763 75%2440 2760 27% 2596 2709 35% 1705 1797 35% 3312 3404 91% 1384 2328HMUAE26 747403 136 WUblastx.64 (Q9P2R4) SEVEN TRANSMEMBRANE Q9P2R4 89%153 575 DOMAIN ORPHAN RECEPTOR. 86% 577 1272 HMUAN45 833072 137WUblastx.64 (BAB55441) CDNA FLJ14993 fis, clone BAB55441 70% 684 1238Y79AA1001874, w 65% 239 955 100% 1247 1516 HMVBC31 825598 138WUblastx.64 (O60725) PROTEIN-S ISOPRENYLCYSTEINE ICMT_HUMAN 80% 747 938O-METHYLTRANSFERASE (E 87% 121 789 HMWBL03 822861 139 WUblastx.64(Q9BWT1) C-MYC TARGET JP1. Q9BWT1 85% 137 1240 HMWCG28 847413 140WUblastx.64 (Q9P1S9) KINASE DEFICIENT PROTEIN Q9P1S9 84% 35 892 KDP(FRAGMENT). HNFCY57 877653 142 WUblastx.64 (AAL12497) Cryopyrin.AAL12497 91% 8 2203 HNGAK51 603910 144 WUblastx.64 (O60448) NEURONALTHREAD PROTEIN O60448 61% 563 601 AD7C-NTP. 67% 733 915 65% 702 878 74%714 914 HNGAM58 688114 145 WUblastx.64 (Q9H728) CDNA: FLJ21463 FIS,CLONE Q9H728 71% 1020 1061 COL04765. 85% 1081 1143 53% 818 1003 HNHFE71834487 155 WUblastx.64 hypothetical protein DKFZp761L0812.1 - humanpir|T47135|T47135 67% 822 583 (fragment) HNHGK22 597451 156 WUblastx.64hypothetical protein (L1H 3′ region) - human pir|B34087|B34087 41% 48337 41% 333 10 50% 733 485 HOACG07 792928 159 WUblastx.64 (Q9GZN8)DJ1009E24.3 (A NOVEL Q9GZN8 99% 183 704 PROTEIN) (CDNA FLJ14158 FIS,CLONE NT2R HOEBK60 789396 161 WUblastx.64 (Q9H916) CDNA FLJ13081 FIS,CLONE Q9H916 98% 132 1916 NT2RP3002033. 100% 14 109 88% 106 159 HOFNB74762821 162 WUblastx.64 (Q99JH1) HYPOTHETICAL 17.7 KDA Q99JH1 72% 44 187PROTEIN. 97% 199 471 HOSDO75 862049 163 WUblastx.64 (Q9D099)1110057L18RIK PROTEIN. Q9D099 89% 11 202 88% 259 630 HOUDE92 580866 165WUblastx.64 (Q9HBT2) HYPOTHETICAL 17.2 KDA Q9HBT2 96% 21 245 PROTEIN.HPFCI36 855966 169 WUblastx.64 (Q9NX47) CDNA FLJ20445 FIS, CLONE Q9NX47100% 9 320 KAT05170. HPRBH85 695752 175 WUblastx.64 (BAB55300) CDNAFLJ14784 fis, clone BAB55300 62% 2 616 NT2RP4000713. 86% 534 1085HPRCD35 853551 176 WUblastx.64 hypothetical protein DKFZp762L1710.1 -human pir|T50629|T50629 100% 320 613 (fragment) 57% 2 499 HPTRM02 812879177 WUblastx.64 (Q9UJU6) SRC HOMOLOGY 3 DOMAIN- Q9UJU6 92% 332 940CONTAINING PROTEIN HIP-55 (DREBRINF). 97% 2 106 96% 98 190 HRADA42827302 178 WUblastx.64 hypothetical protein C11D2.4 - Caenorhabditispir|T32961|T32961 48% 387 668 elegans 74% 668 931 HRADF49 866481 179WUblastx.64 (Q9H6L1) CDNA: FLJ22169 FIS, CLONE Q9H6L1 90% 13 825HRC00632. 84% 813 1379 75% 1291 1593 34% 1590 1685 HRADN25 800628 180WUblastx.64 (Q9HB07) MYG1 PROTEIN. MYG1_HUMAN 96% 47 1174 HRDDQ39 840405181 WUblastx.64 (Q9NX85) CDNA FLJ20378 FIS, CLONE Q9NX85 53% 582 436KAIA0536. 65% 775 578 HRDER22 688056 182 WUblastx.64 (Q9NW07) CDNAFLJ10390 FIS, CLONE Q9NW07 80% 9 248 NT2RM4000104, MODERATELY SIMILAR100% 357 431 TO 39% 120 227 28% 15 203 38% 254 316 HRDEX93 816046 183WUblastx.64 (Q9UBV8) PEFLIN. Q9UBV8 100% 313 864 HRDFK37 840381 184WUblastx.64 (Q9P195) PRO1722. Q9P195 69% 536 652 40% 50 115 HRTAP63780698 185 WUblastx.64 (Q9Y3C9) CGI-127 PROTEIN. Q9Y3C9 100% 498 860HSAVA08 580870 186 WUblastx.64 (Q9BGW3) HYPOTHETICAL 13.5 KDA Q9BGW3 57%949 896 PROTEIN. 42% 926 792 63% 796 764 66% 1059 934 HSDZM54 637870 189WUblastx.64 NADH dehydrogenase (ubiquinone) (EC 1.6.5.3)pir|A00422|DNHUN3 88% 226 360 chain 3 - human mitochondrion HSHBF76715838 190 WUblastx.64 (AAH08335) Unknown (protein for AAH08335 86% 762457 IMAGE: 3506202) (Fra 73% 882 748 100% 1267 836 HSJBY32 702020 192WUblastx.64 (Q9GZZ6) NEURONAL NICOTINIC Q9GZZ6 81% 466 639 ACETYLCHOLINEALPHA10 SUBUNIT 57% 215 514 PRECURSOR ( HSNBM34 635131 195 WUblastx.64acyl-CoA dehydrogenase (EC 1.3.99.—) very- pir|S54183|S54183 84% 15481979 long-chain specific - human 100% 251 1546 HSQDO85 853393 196WUblastx.64 (Q9VCK0) CG10161 PROTEIN. Q9VCK0 67% 485 988 60% 60 521 56%10 57 HSRBE06 871264 197 WUblastx.64 (Q9H387) PRO2550. Q9H387 70% 16081327 HSSDI26 560722 198 WUblastx.64 (Q9BVD9) UNKNOWN (PROTEIN FOR Q9BVD968% 1398 1264 MGC: 5149). HSSEA64 853395 199 WUblastx.64 (Q9HBT2)HYPOTHETICAL 17.2 KDA Q9HBT2 98% 7 243 PROTEIN. HSSEF77 658725 200WUblastx.64 (O95637) WW DOMAIN BINDING PROTEIN- O95637 42% 10 246 1. 83%296 829 HSSFE38 742512 201 HMMER PFAM: Ribonuclease HII PF01351 76.3 184−142 2.1.1 WUblastx.64 (O75792) RIBONUCLEASE HI LARGE RNHL_HUMAN 91% 156635 SUBUNIT (EC 3.1.26.—) (RNASE 99% 587 1051 HSXCP38 895392 202WUblastx.64 hydroxymethylglutaryl-CoA lyase (EC 4.1.3.4) -pir|B45470|B45470 70% 17 895 chicken HT5GR59 801930 205 WUblastx.64(O60496) DOCKING PROTEIN. O60496 72% 70 1284 HTEAG62 812332 206WUblastx.64 (Q9Y5Z7) HOST CELL FACTOR 2. Q9Y5Z7 60% 1 57 93% 14 2011 30%107 631 HTEEW69 764835 207 WUblastx.64 (Q9Z1H7) GSG1. Q9Z1H7 65% 850 92785% 707 769 50% 519 662 66% 908 943 65% 182 544 HTEGS07 827700 208WUblastx.64 (Q9D143) 1110030K22RIK PROTEIN. Q9D143 96% 183 593 HTEJD29695798 211 WUblastx.64 (Q60713) REVERSE TRANSCRIPTASE. Q60713 42% 11151285 47% 874 1089 HTENR63 877952 213 WUblastx.64 (Q9HD71) HYPOTHETICALNUCLEAR Q9HD71 33% 1278 1358 FACTOR SBBI22. 78% 26 1168 HTGGM44 842856214 WUblastx.64 probable phosphodiesterase I (EC 3.1.4.1) -pir|T43461|T43461 100% 1400 1924 human (fragment) 83% 1925 2488 HTLBT80840045 217 WUblastx.64 (Q9NQQ7) BA394O2.1 (CGI-15 PROTEIN). Q9NQQ7 76%1214 1405 74% 804 1223 47% 780 845 78% 313 825 HTLEM16 779133 219WUblastx.64 (O95638) WW DOMAIN BINDING PROTEIN- O95638 92% 50 541 2. 28%987 1142 48% 617 841 HTLFA13 535937 220 WUblastx.64 (Q9UHT1) PRO1902PROTEIN. Q9UHT1 57% 1118 873 HTLGI89 835069 221 WUblastx.64 (Q9BXS5)CLATHRIN-ASSOCIATED Q9BXS5 98% 104 682 PROTEIN AP47. 99% 675 1370HTLIF11 843506 222 WUblastx.64 (Q9I8S4) ORNITHINE DECARBOXYLASE-2.Q9I8S4 68% 309 356 59% 353 1687 HTNBK13 831967 223 WUblastx.64 (Q9Y3M2)HYPOTHETICAL 14.5 KDA Q9Y3M2 81% 123 500 PROTEIN. HTOAM11 664508 224WUblastx.64 (Q9H5R3) CDNA: FLJ23147 FIS, CLONE Q9H5R3 77% 428 363LNG09295. 75% 586 425 HTPCO75 853645 226 WUblastx.64 (O00549) ORF2-LIKEPROTEIN O00549 43% 325 26 (FRAGMENT). 36% 1318 1253 HTSFJ32 637720 227WUblastx.64 (Q9WUW2) VESICLE ASSOCIATED Q9WUW2 64% 747 788 MEMBRANEPROTEIN 2B. 94% 448 609 HTTCB60 853401 228 WUblastx.64 (Q9HAW0) RNAPOLYMERASE III Q9HAW0 90% 6 881 TRANSCRIPTION INITIATION FACTOR BRFU.HTTEE41 840950 229 WUblastx.64 (P78371) T-COMPLEX PROTEIN 1, BETATCPB_HUMAN 98% 92 1696 SUBUNIT (TCP-1-BETA) (CC HTTEZ02 702027 230WUblastx.64 (Q9UEZ7) MAKORIN 1. Q9UEZ7 56% 278 346 98% 6 272 HTWEH94561680 231 WUblastx.64 (Q9GMX5) HYPOTHETICAL 12.9 KDA Q9GMX5 60% 1150929 PROTEIN. HTXDC77 844258 232 HMMER PFAM: Class I Histocompatibilityantigen, PF00129 103.3 137 259 2.1.1 domains alpha 1 and 2 WUblastx.64(P03989) HLA CLASS I 1B14_HUMAN 63% 880 945 HISTOCOMPATIBILITY ANTIGEN,B-27 71% 65 256 ALPHA 80% 282 863 HTXFA72 853410 235 WUblastx.64(Q9N083) UNNAMED PORTEIN PRODUCT. Q9N083 59% 1688 1557 66% 1839 1681HTXMZ07 834881 237 WUblastx.64 (Q9BRF3) SIMILAR TO RIKEN CDNA Q9BRF3 90%3 1469 2810468K17 GENE. HUKBT67 844446 238 WUblastx.64 (BAB55428) CDNAFLJ14975 fis, clone BAB55428 100% 1040 1216 THYRO1001405, w 100% 8 6130% 80 241 HUSCJ14 894699 240 WUblastx.64 tex261 protein - mousepir|S47481|S47481 99% 74 661 HUSGL67 792637 241 WUblastx.64 (Q9Y2G2)CARD DOMAIN PROTEIN 8 CRD8_HUMAN 100% 347 421 (APOPTOTIC PROTEIN NDPP1)(D 65% 947 1006 97% 469 954 HUSGU40 684975 242 WUblastx.64 (Q9BX98)UBIQUITIN A-52 RESIDUE Q9BX98 75% 840 433 RIBOSOMAL PROTEIN FUSIONPRODUCT 1 (F HUVDJ48 564853 244 WUblastx.64 SHORT ISOFORM OF Q9P2N4sp_vs|Q9P2N4- 92% 1510 1668 01|Q9P2N4 HWDAC26 821335 245 WUblastx.64(Q14287) HYPOTHETICAL PROTEIN Q14287 51% 1316 1471 (FRAGMENT). 57% 10931323 HBDAB91 864374 247 WUblastx.64 (O00370) PUTATIVE P150. O00370 40%907 833 35% 849 307 HBDAB91 789532 255 WUblastx.64 (O00370) PUTATIVEP150. O00370 40% 587 513 34% 529 5 HILCA24 869856 248 WUblastx.64(Q9NUU6) CDNA FLJ11127 FIS, CLONE Q9NUU6 95% 104 1171 PLACE1006225.HILCA24 782450 256 WUblastx.64 (Q9NUU6) CDNA FLJ11127 FIS, CLONE Q9NUU673% 103 159 PLACE1006225. 100% 168 1169 HYABC84 865064 249 WUblastx.64(Q9H429) DJ756N5.2 (A NOVEL PROTEIN Q9H429 92% 163 618 (DKFZP727M231)SIMILAR TO TRP4-AS HYABC84 789854 257 WUblastx.64 (Q99L03) SIMILAR TOTRP4-ASSOCIATED Q99L03 89% 209 553 PROTEIN TAP1 (FRAGMENT). HE2CA60888705 250 WUblastx.64 (O95232) OKADAIC ACID-INDUCIBLE OA48_HUMAN 98%1098 1265 PHOSPHOPROTEIN OA48-18. HPQAX38 845752 251 WUblastx.64(Q9BGV8) HYPOTHETICAL 10.0 KDA Q9BGV8 74% 664 768 PROTEIN. 68% 543 674HPQAX38 843592 259 WUblastx.64 (Q9BGV8) HYPOTHETICAL 10.0 KDA Q9BGV8 74%664 768 PROTEIN. 68% 543 674RACE Protocol For Recovery of Full-Length Genes

Partial cDNA clones can be made full-length by utilizing the rapidamplification of cDNA ends (RACE) procedure described in Frohman, M. A.,et al., Proc. Nat'l. Acad. Sci. USA, 85:8998-9002 (1988). A cDNA clonemissing either the 5′ or 3′ end can be reconstructed to include theabsent base pairs extending to the translational start or stop codon,respectively. In some cases, cDNAs are missing the start codon oftranslation, therefor. The following briefly describes a modification ofthis original 5′ RACE procedure. Poly A+ or total RNA is reversetranscribed with Superscript II (Gibco/BRL) and an antisense orcomplementary primer specific to the cDNA sequence. The primer isremoved from the reaction with a Microcon Concentrator (Amicon). Thefirst-strand cDNA is then tailed with dATP and terminal deoxynucleotidetransferase (Gibco/BRL). Thus, an anchor sequence is produced which isneeded for PCR amplification. The second strand is synthesized from thedA-tail in PCR buffer, Taq DNA polymerase (Perkin-Elmer Cetus), anoligo-dT primer containing three adjacent restriction sites (XhoI, SalIand ClaI) at the 5′ end and a primer containing just these restrictionsites. This double-stranded cDNA is PCR amplified for 40 cycles with thesame primers as well as a nested cDNA-specific antisense primer. The PCRproducts are size-separated on an ethidium bromide-agarose gel and theregion of gel containing cDNA products the predicted size of missingprotein-coding DNA is removed. cDNA is purified from the agarose withthe Magic PCR Prep kit (Promega), restriction digested with XhoI orSalI, and ligated to a plasmid such as pBluescript SKII (Stratagene) atXhoI and EcORV sites. This DNA is transformed into bacteria and theplasmid clones sequenced to identify the correct protein-coding inserts.Correct 5′ ends are confirmed by comparing this sequence with theputatively identified homologue and overlap with the partial cDNA clone.Similar methods known in the art and/or commercial kits are used toamplify and recover 3′ ends.

Several quality-controlled kits are commercially available for purchase.Similar reagents and methods to those above are supplied in kit formfrom Gibco/BRL for both 5′ and 3′ RACE for recovery of full lengthgenes. A second kit is available from Clontech which is a modificationof a related technique, SLIC (single-stranded ligation tosingle-stranded cDNA), developed by Dumas et al., Nucleic Acids Res.,19:5227-32 (1991). The major differences in procedure are that the RNAis alkaline hydrolyzed after reverse transcription and RNA ligase isused to join a restriction site-containing anchor primer to thefirst-strand cDNA. This obviates the necessity for the dA-tailingreaction which results in a polyT stretch that is difficult to sequencepast.

An alternative to generating 5′ or 3′ cDNA from RNA is to use cDNAlibrary double-stranded DNA. An asymmetric PCR-amplified antisense cDNAstrand is synthesized with an, antisense cDNA-specific primer and aplasmid-anchored primer. These primers are removed and a symmetric PCRreaction is performed with a nested cDNA-specific antisense primer andthe plasmid-anchored primer.

RNA Ligase Protocol For Generating The 5′ or 3′ End Sequences To ObtainFull Length Genes

Once a gene of interest is identified, several methods are available forthe identification of the 5′ or 3′ portions of the gene which may not bepresent in the original cDNA plasmid. These methods include, but are notlimited to, filter probing, clone enrichment using specific probes andprotocols similar and identical to 5′ and 3′ RACE. While the full lengthgene may be present in the library and can be identified by probing, auseful method for generating the 5′ or 3′ end is to use the existingsequence information from the original cDNA to generate the missinginformation. A method similar to 5′ RACE is available for generating themissing 5′ end of a desired full-length gene. (This method was publishedby Fromont-Racine et al., Nucleic Acids Res., 21(7):1683-1684 (1993)).Briefly, a specific RNA oligonucleotide is ligated to the 5′ ends of apopulation of RNA presumably containing full-length gene RNA transcriptand a primer set containing a primer specific to the ligated RNAoligonucleotide and a primer specific to a known sequence of the gene ofinterest, is used to PCR amplify the 5′ portion of the desired fulllength gene which may then be sequenced and used to generate the fulllength gene. This method starts with total RNA isolated from the desiredsource, poly A RNA may be used but is not a prerequisite for thisprocedure. The RNA preparation may then be treated with phosphatase ifnecessary to eliminate 5′ phosphate groups on degraded or damaged RNAwhich may interfere with the later RNA ligase step. The phosphatase ifused is then inactivated and the RNA is treated with tobacco acidpyrophosphatase in order to remove the cap structure present at the 5′ends of messenger RNAs. This reaction leaves a 5′ phosphate group at the5′ end of the cap cleaved RNA which can then be ligated to an RNAoligonucleotide using T4 RNA ligase. This modified RNA preparation canthen be used as a template for first strand cDNA synthesis using a genespecific oligonucleotide. The first strand synthesis reaction can thenbe used as a template for PCR amplification of the desired 5′ end usinga primer specific to the ligated RNA oligonucleotide and a primerspecific to the known sequence of the gene of interest. The resultantproduct is then sequenced and analyzed to confirm that the 5′ endsequence belongs to the relevant gene.

The present invention also relates to vectors or plasmids which includesuch DNA sequences, as well as the use of the DNA sequences. Thematerial deposited with the ATCC (e.g., as described in columns 2 and 3of Table 1A, and/or as set forth in Table 1B, Table 6, or Table 7) is amixture of cDNA clones derived from a variety of human tissue and clonedin either a plasmid vector or a phage vector, as described, for example,in Table 1A and Table 7. These deposits are referred to as “thedeposits” herein. The tissues from which some of the clones were derivedare listed in Table 7, and the vector in which the corresponding cDNA iscontained is also indicated in Table 7. The deposited material includescDNA clones corresponding to SEQ ID NO:X described, for example, inTable 1A and/or Table 1B (ATCC Deposit No:Z). A clone which isisolatable from the ATCC Deposits by use of a sequence listed as SEQ IDNO:X, may include the entire coding region of a human gene or in othercases such clone may include a substantial portion of the coding regionof a human gene. Furthermore, although the sequence listing may in someinstances list only a portion of the DNA sequence in a clone included inthe ATCC Deposits, it is well within the ability of one skilled in theart to sequence the DNA included in a clone contained in the ATCCDeposits by use of a sequence (or portion thereof) described in, forexample Tables 1A and/or Table 1B or Table 2, by procedures hereinafterfurther described, and others apparent to those skilled in the art.

Also provided in Table 1A and Table 7 is the name of the vector whichcontains the cDNA clone. Each vector is routinely used in the art. Thefollowing additional information is provided for convenience.

Vectors Lambda Zap (U.S. Pat. Nos. 5,128,256 and 5,286,636), Uni-Zap XR(U.S. Pat. Nos. 5,128,256 and 5,286,636), Zap Express (U.S. Pat. Nos.5,128,256 and 5,286,636), pBluescript (pBS) (Short, J. M. et al.,Nucleic Acids Res. 16:7583-7600 (1988); Alting-Mees, M. A. and Short, J.M., Nucleic Acids Res. 17:9494 (1989)) and pBK (Alting-Mees, M. A. etal., Strategies 5:58-61 (1992)) are commercially available fromStratagene Cloning Systems, Inc., 11011 N. Torrey Pines Road, La Jolla,Calif., 92037. pBS contains an ampicillin resistance gene and pBKcontains a neomycin resistance gene. Phagemid pBS may be excised fromthe Lambda Zap and Uni-Zap XR vectors, and phagemid pBK may be excisedfrom the Zap Express vector. Both phagemids may be transformed into E.coli strain XL-1 Blue, also available from Stratagene.

Vectors pSport1, pCMVSport 1.0, pCMVSport 2.0 and pCMVSport 3.0, wereobtained from Life Technologies, Inc., P.O. Box 6009, Gaithersburg, Md.20897. All Sport vectors contain an ampicillin resistance gene and maybe transformed into E. coli strain DH10B, also available from LifeTechnologies. See, for instance, Gruber, C. E., et al., Focus 15:59-(1993). Vector lafmid BA (Bento Soares, Columbia University, New York,N.Y.) contains an ampicillin resistance gene and can be transformed intoE. coli strain XL-1 Blue. Vector pCR®2.1, which is available fromInvitrogen, 1600 Faraday Avenue, Carlsbad, Calif. 92008, contains anampicillin resistance gene and may be transformed into E. coli strainDH10B, available from Life Technologies. See, for instance, Clark, J.M., Nuc. Acids Res. 16:9677-9686 (1988) and Mead, D. et al.,Bio/Technology 9: (1991).

The present invention also relates to the genes corresponding to SEQ IDNO:X, SEQ ID NO:Y, and/or the deposited clone (ATCC Deposit No:Z). Thecorresponding gene can be isolated in accordance with known methodsusing the sequence information disclosed herein. Such methods includepreparing probes or primers from the disclosed sequence and identifyingor amplifying the corresponding gene from appropriate sources of genomicmaterial.

Also provided in the present invention are allelic variants, orthologs,and/or species homologs. Procedures known in the art can be used toobtain full-length genes, allelic variants, splice variants, full-lengthcoding portions, orthologs, and/or species homologs of genescorresponding to SEQ ID NO:X or the complement thereof, polypeptidesencoded by genes corresponding to SEQ ID NO:X or the complement thereof,and/or the cDNA contained in ATCC Deposit No:Z, using information fromthe sequences disclosed herein or the clones deposited with the ATCC.For example, allelic variants and/or species homologs may be isolatedand identified by making suitable probes or primers from the sequencesprovided herein and screening a suitable nucleic acid source for allelicvariants and/or the desired homologue.

The polypeptides of the invention can be prepared in any suitablemanner. Such polypeptides include isolated naturally occurringpolypeptides, recombinantly produced polypeptides, syntheticallyproduced polypeptides, or polypeptides produced by a combination ofthese methods. Means for preparing such polypeptides are well understoodin the art

The polypeptides may be in the form of the secreted protein, includingthe mature form, or may be a part of a larger protein, such as a fusionprotein (see below). It is often advantageous to include an additionalamino acid sequence which contains secretory or leader sequences,pro-sequences, sequences which aid in purification, such as multiplehistidine residues, or an additional sequence for stability duringrecombinant production.

The polypeptides of the present invention are preferably provided in anisolated form, and preferably are substantially purified. Arecombinantly produced version of a polypeptide, including the secretedpolypeptide, can be substantially purified using techniques describedherein or otherwise known in the art, such as, for example, by theone-step method described in Smith and Johnson, Gene 67:3140 (1988).Polypeptides of the invention also can be purified from natural,synthetic or recombinant sources using techniques described herein orotherwise known in the art, such as, for example, antibodies of theinvention raised against the polypeptides of the present invention inmethods which are well known in the art.

The present invention provides a polynucleotide comprising, oralternatively consisting of, the nucleic acid sequence of SEQ ID NO:X,and/or the cDNA sequence contained in ATCC Deposit No:Z. The presentinvention also provides a polypeptide comprising, or alternatively,consisting of, the polypeptide sequence of SEQ ID NO:Y, a polypeptideencoded by SEQ ID NO:X or a complement thereof, a polypeptide encoded bythe cDNA contained in ATCC Deposit No:Z, and/or the polypeptide sequenceencoded by a nucleotide sequence in SEQ ID NO:B as defined in column 6of Table 1C. Polynucleotides encoding a polypeptide comprising, oralternatively consisting of the polypeptide sequence of SEQ ID NO:Y, apolypeptide encoded by SEQ ID NO:X, a polypeptide encoded by the cDNAcontained in ATCC Deposit No:Z, and/or a polypeptide sequence encoded bya nucleotide sequence in SEQ ID NO:B as defined in column 6 of Table 1Care also encompassed by the invention. The present invention furtherencompasses a polynucleotide comprising, or alternatively consisting of,the complement of the nucleic acid sequence of SEQ ID NO:X, a nucleicacid sequence encoding a polypeptide encoded by the complement of thenucleic acid sequence of SEQ ID NO:X, and/or the cDNA contained in ATCCDeposit No:Z.

Moreover, representative examples of polynucleotides of the inventioncomprise, or alternatively consist of, one, two, three, four, five, six,seven, eight, nine, ten, or more of the sequences delineated in Table 1Ccolumn 6, or any combination thereof. Additional, representativeexamples of polynucleotides of the invention comprise, or alternativelyconsist of, one, two, three, four, five, six, seven, eight, nine, ten,or more of the complementary strand(s) of the sequences delineated inTable 1C column 6, or any combination thereof. In further embodiments,the above-described polynucleotides of the invention comprise, oralternatively consist of, sequences delineated in Table 1C, column 6,and have a nucleic acid sequence which is different from that of the BACfragment having the sequence disclosed in SEQ ID NO:B (see Table 1C,column 5). In additional embodiments, the above-describedpolynucleotides of the invention comprise, or alternatively consist of,sequences delineated in Table 1C, column 6, and have a nucleic acidsequence which is different from that published for the BAC cloneidentified as BAC ID NO:A (see Table 1C, column 4). In additionalembodiments, the above-described polynucleotides of the inventioncomprise, or alternatively consist of, sequences delineated in Table 1C,column 6, and have a nucleic acid sequence which is different from thatcontained in the BAC clone identified as BAC ID NO:A (see Table 1C,column 4). Polypeptides encoded by these polynucleotides, otherpolynucleotides that encode these polypeptides, and antibodies that bindthese polypeptides are also encompassed by the invention. Additionally,fragments and variants of the above-described polynucleotides andpolypeptides are also encompassed by the invention.

Further, representative examples of polynucleotides of the inventioncomprise, or alternatively consist of, one, two, three, four, five, six,seven, eight, nine, ten, or more of the sequences delineated in column 6of Table 1C which correspond to the same Clone ID (see Table 1C, column1), or any combination thereof. Additional, representative examples ofpolynucleotides of the invention comprise, or alternatively consist of,one, two, three, four, five, six, seven, eight, nine, ten, or more ofthe complementary strand(s) of the sequences delineated in column 6 ofTable 1C which correspond to the same Clone ID (see Table 1C, column 1),or any combination thereof. In further embodiments, the above-describedpolynucleotides of the invention comprise, or alternatively consist of,sequences delineated in column 6 of Table 1C which correspond to thesame Clone ID (see Table 1C, column 1) and have a nucleic acid sequencewhich is different from that of the BAC fragment having the sequencedisclosed in SEQ ID NO:B (see Table 1C, column 5). In additionalembodiments, the above-described polynucleotides of the inventioncomprise, or alternatively consist of, sequences delineated in column 6of Table 1C which correspond to the same Clone ID (see Table 1C,column 1) and have a nucleic acid sequence which is different from thatpublished for the BAC clone identified as BAC ID NO:A (see Table 1C,column 4). In additional embodiments, the above-describedpolynucleotides of the invention comprise, or alternatively consist of,sequences delineated in column 6 of Table 1C which correspond to thesame Clone ID (see Table 1C, column 1) and have a nucleic acid sequencewhich is different from that contained in the BAC clone identified asBAC ID NO:A (see Table 1C, column 4). Polypeptides encoded by thesepolynucleotides, other polynucleotides that encode these polypeptides,and antibodies that bind these polypeptides are also encompassed by theinvention. Additionally, fragments and variants of the above-describedpolynucleotides and polypeptides are also encompassed by the invention.

Further, representative examples of polynucleotides of the inventioncomprise, or alternatively consist of, one, two, three, four, five, six,seven, eight, nine, ten, or more of the sequences delineated in column 6of Table 1C which correspond to the same contig sequence identifier SEQID NO:X (see Table 1C, column 2), or any combination thereof.Additional, representative examples of polynucleotides of the inventioncomprise, or alternatively consist of, one, two, three, four, five, six,seven, eight, nine, ten, or more of the complementary strand(s) of thesequences delineated in column 6 of Table 1C which correspond to thesame contig sequence identifier SEQ ID NO:X (see Table 1C, column 2), orany combination thereof. In further embodiments, the above-describedpolynucleotides of the invention comprise, or alternatively consist of,sequences delineated in column 6 of Table 1C which correspond to thesame contig sequence identifier SEQ ID NO:X (see Table 1C, column 2) andhave a nucleic acid sequence which is different from that of the BACfragment having the sequence disclosed in SEQ ID NO:B (see Table 1C,column 5). In additional embodiments, the above-describedpolynucleotides of the invention comprise, or alternatively consist of,sequences delineated in column 6 of Table 1C which correspond to thesame contig sequence identifier SEQ ID NO:X (see Table 1C, column 2) andhave a nucleic acid sequence which is different from that published forthe BAC clone identified as BAC ID NO:A (see Table 1C, column 4). Inadditional embodiments, the above-described polynucleotides of theinvention comprise, or alternatively consist of, sequences delineated incolumn 6 of Table 1C which correspond to the same contig sequenceidentifier SEQ ID NO:X (see Table 1C, column 2) and have a nucleic acidsequence which is different from that contained in the BAC cloneidentified as BAC ID NO:A (See Table 1C, column 4). Polypeptides encodedby these polynucleotides, other polynucleotides that encode thesepolypeptides, and antibodies that bind these polypeptides are alsoencompassed by the invention. Additionally, fragments and variants ofthe above-described polynucleotides and polypeptides are alsoencompassed by the invention.

Moreover, representative examples of polynucleotides of the inventioncomprise, or alternatively consist of, one, two, three, four, five, six,seven, eight, nine, ten, or more of the sequences delineated in the samerow of Table 1C. column 6, or any combination thereof. Additional,representative examples of polynucleotides of the invention comprise, oralternatively consist of, one, two, three, four, five, six, seven,eight, nine, ten, or more of the complementary strand(s) of thesequences delineated in the same row of Table 1C column 6, or anycombination thereof. In preferred embodiments, the polynucleotides ofthe invention comprise, or alternatively consist of, one, two, three,four, five, six, seven, eight, nine, ten, or more of the complementarystrand(s) of the sequences delineated in the same row of Table 1C column6, wherein sequentially delineated sequences in the table (i.e.corresponding to those exons located closest to each other) are directlycontiguous in a 5′ to 3′ orientation. In further embodiments,above-described polynucleotides of the invention comprise, oralternatively consist of, sequences delineated in the same row of Table1C, column 6, and have a nucleic acid sequence which is different fromthat of the BAC fragment having the sequence disclosed in SEQ ID NO:B(see Table 1C, column 5). In additional embodiments, the above-describedpolynucleotides of the invention comprise, or alternatively consist of,sequences delineated in the same row of Table 1C, column 6, and have anucleic acid sequence which is different from that published for the BACclone identified as BAC ID NO:A (see Table 1C, column 4). In additionalembodiments, the above-described polynucleotides of the inventioncomprise, or alternatively consist of, sequences delineated in the samerow of Table 1C, column 6, and have a nucleic acid sequence which isdifferent from that contained in the BAC clone identified as BAC ID NO:A(see Table 1C, column 4). Polypeptides encoded by these polynucleotides,other polynucleotides that encode these polypeptides, and antibodiesthat bind these polypeptides are also encompassed by the invention.

In additional specific embodiments, polynucleotides of the inventioncomprise, or alternatively consist of, one, two, three, four, five, six,seven, eight, nine, ten, or more of the sequences delineated in column 6of Table 1C, and the polynucleotide sequence of SEQ ID NO:X (e.g., asdefined in Table 1C, column 2) or fragments or variants thereof.Polypeptides encoded by these polynucleotides, other polynucleotidesthat encode these polypeptides, and antibodies that bind thesepolypeptides are also encompassed by the invention.

In additional specific embodiments, polynucleotides of the inventioncomprise, or alternatively consist of, one, two, three, four, five, six,seven, eight, nine, ten, or more of the sequences delineated in column 6of Table 1C which correspond to the same Clone ID (see Table 1C, column1), and the polynucleotide sequence of SEQ ID NO:X (e.g., as defined inTable 1A, Table 1B, or Table 1C) or fragments or variants thereof. Inpreferred embodiments, the delineated sequence(s) and polynucleotidesequence of SEQ ID NO:X correspond to the same Clone ID. Polypeptidesencoded by these polynucleotides, other polynucleotides that encodethese polypeptides, and antibodies that bind these polypeptides are alsoencompassed by the invention.

In further specific embodiments, polynucleotides of the inventioncomprise, or alternatively consist of, one, two, three, four, five, six,seven, eight, nine, ten, or more of the sequences delineated in the samerow of column 6 of Table 1C, and the polynucleotide sequence of SEQ IDNO:X (e.g., as defined in Table 1A, Table 1B, or Table 1C) or fragmentsor variants thereof. In preferred embodiments, the delineatedsequence(s) and polynucleotide sequence of SEQ ID NO:X correspond to thesame row of column 6 of Table 1C. Polypeptides encoded by thesepolynucleotides, other polynucleotides that encode these polypeptides,and antibodies that bind these polypeptides are also encompassed by theinvention.

In additional specific embodiments, polynucleotides of the inventioncomprise, or alternatively consist of a polynucleotide sequence in whichthe 3′ 10 polynucleotides of one of the sequences delineated in column 6of Table 1C and the 5′ 10 polynucleotides of the sequence of SEQ ID NO:Xare directly contiguous. Nucleic acids which hybridize to the complementof these 20 contiguous polynucleotides under stringent hybridizationconditions or alternatively, under lower stringency conditions, are alsoencompassed by the invention. Polypeptides encoded by thesepolynucleotides and/or nucleic acids, other polynucleotides and/ornucleic acids that encode these polypeptides, and antibodies that bindthese polypeptides are also encompassed by the invention. Additionally,fragments and variants of the above-described polynucleotides, nucleicacids, and polypeptides are also encompassed by the invention.

In additional specific embodiments, polynucleotides of the inventioncomprise, or alternatively consist of, a polynucleotide sequence inwhich the 3′ 10 polynucleotides of one of the sequences delineated incolumn 6 of Table 1C and the 5′ 10 polynucleotides of a fragment orvariant of the sequence of SEQ ID NO:X are directly contiguous Nucleicacids which hybridize to the complement of these 20 contiguouspolynucleotides under stringent hybridization conditions oralternatively, under lower stringency conditions, are also encompassedby the invention. Polypeptides encoded by these polynucleotides and/ornucleic acids, other polynucleotides and/or nucleic acids encoding thesepolypeptides, and antibodies that bind these polypeptides are alsoencompassed by the invention. Additionally, fragments and variants ofthe above-described polynucleotides, nucleic acids, and polypeptides arealso encompassed by the invention.

In specific embodiments, polynucleotides of the invention comprise, oralternatively consist of, a polynucleotide sequence in which the 3′ 10polynucleotides of the sequence of SEQ ID NO:X and the 5′ 10polynucleotides of the sequence of one of the sequences delineated incolumn 6 of Table 1C are directly contiguous. Nucleic acids whichhybridize to the complement of these 20 contiguous polynucleotides understringent hybridization conditions or alternatively, under lowerstringency conditions, are also encompassed by the invention.Polypeptides encoded by these polynucleotides and/or nucleic acids,other polynucleotides and/or nucleic acids encoding these polypeptides,and antibodies that bind these polypeptides are also encompassed by theinvention. Additionally, fragments and variants of the above-describedpolynucleotides, nucleic acids, and polypeptides are also encompassed bythe invention.

In specific embodiments, polynucleotides of the invention comprise, oralternatively consist of, a polynucleotide sequence in which the 3′ 10polynucleotides of a fragment or variant of the sequence of SEQ ID NO:Xand the 5′ 10 polynucleotides of the sequence of one of the sequencesdelineated in column 6 of Table 1C are directly contiguous. Nucleicacids which hybridize to the complement of these 20 contiguouspolynucleotides under stringent hybridization conditions oralternatively, under lower stringency conditions, are also encompassedby the invention. Polypeptides encoded by these polynucleotides and/ornucleic acids, other polynucleotides and/or nucleic acids encoding thesepolypeptides, and antibodies that bind these polypeptides are alsoencompassed by the invention. Additionally, fragments and variants ofthe above-described polynucleotides, nucleic acids, and polypeptides,are also encompassed by the invention.

In further specific embodiments, polynucleotides of the inventioncomprise, or alternatively consist of, a polynucleotide sequence inwhich the 3′ 10 polynucleotides of one of the sequences delineated incolumn 6 of Table 1C and the 5′ 10 polynucleotides of another sequencein column 6 are directly contiguous. Nucleic acids which hybridize tothe complement of these 20 contiguous polynucleotides under stringenthybridization conditions or alternatively, under lower stringencyconditions, are also encompassed by the invention. Polypeptides encodedby these polynucleotides and/or nucleic acids, other polynucleotidesand/or nucleic acids encoding these polypeptides, and antibodies thatbind these polypeptides are also encompassed by the invention.Additionally, fragments and variants of the above-describedpolynucleotides, nucleic acids, and polypeptides are also encompassed bythe invention.

In specific embodiments, polynucleotides of the invention comprise, oralternatively consist of, a polynucleotide sequence in which the 3′ 10polynucleotides of one of the sequences delineated in column 6 of Table1C and the 5′ 10 polynucleotides of another sequence in column 6corresponding to the same Clone ID (see Table 1C, column 1) are directlycontiguous. Nucleic acids which hybridize to the complement of these 20lower stringency conditions, are also encompassed by the invention.Polypeptides encoded by these polynucleotides and/or nucleic acids,other polynucleotides and/or nucleic acids encoding these polypeptides,and antibodies that bind these polypeptides are also encompassed by theinvention. Additionally, fragments and variants of the above-describedpolynucleotides, nucleic acids, and polypeptides are also encompassed bythe invention.

In specific embodiments, polynucleotides of the invention comprise, oralternatively consist of, a polynucleotide sequence in which the 3′ 10polynucleotides of one sequence in column 6 corresponding to the samecontig sequence identifer SEQ ID NO:X (see Table 1C, column 2) aredirectly contiguous. Nucleic acids which hybridize to the complement ofthese 20 contiguous polynucleotides under stringent hybridizationconditions or alternatively, under lower stringency conditions, are alsoencompassed by the invention. Polypeptides encoded by thesepolynucleotides and/or nucleic acids, other polynucleotides and/ornucleic acids encoding these polypeptides, and antibodies that bindthese polypeptides are also encompassed by the invention. Additionally,fragments and variants of the above-described polynucleotides, nucleicacids, and polypeptides are also encompassed by the invention.

In specific embodiments, polynucleotides of the invention comprise, oralternatively consist of a polynucleotide sequence in which the 3′ 10polynucleotides of one of the sequences delineated in column 6 of Table1C and the 5′ 10 polynucleotides of another sequence in column 6corresponding to the same row are directly contiguous. In preferredembodiments, the 3′ 10 polynucleotides of one of the sequencesdelineated in column 6 of Table 1C is directly contiguous with the 5′ 10polynucleotides of the next sequential exon delineated in Table 1C,column 6. Nucleic acids which hybridize to the complement of these 20contiguous polynucleotides under stringent hybridization conditions oralternatively, under lower stringency conditions, are also encompassedby the invention. Polypeptides encoded by these polynucleotides and/ornucleic acids, other polynucleotides and/or nucleic acids encoding thesepolypeptides, and antibodies that bind these polypeptides are alsoencompassed by the invention. Additionally, fragments and variants ofthe above-described polynucleotides, nucleic acids, and polypeptides arealso encompassed by the invention.

Table 3

Many polynucleotide sequences, such as EST sequences, are publiclyavailable and accessible through sequence databases and may have beenpublicly available prior to conception of the present invention.Preferably, such related polynucleotides are specifically excluded fromthe scope of the present invention. Accordingly, for each contigsequence (SEQ ID NO:X) listed in the fifth column of Table 1A and/orTable 1B, preferably excluded are one or more polynucleotides comprisinga nucleotide sequence described by the general formula of a-b, where ais any integer between 1 and the final nucleotide minus 15 of SEQ IDNO:X, b is an integer of 15 to the final nucleotide of SEQ ID NO:X,where both a and b correspond to the positions of nucleotide residuesshown in SEQ ID NO:X, and where b is greater than or equal to a +14.More specifically, preferably excluded are one or more polynucleotidescomprising a nucleotide sequence described by the general formula ofa-b, where a and b are integers as defined in columns 4 and 5,respectively, of Table 3. In specific embodiments, the polynucleotidesof the invention do not consist of at least one, two, three, four, five,ten, or more of the specific polynucleotide sequences referenced by theGenbank Accession No. as disclosed in column 6 of Table 3 (including forexample, published sequence in connection with a particular BAC clone).In further embodiments, preferably excluded from the invention are thespecific polynucleotide sequence(s) contained in the clonescorresponding to at least one, two, three, four, five, ten, or more ofthe available material having the accession numbers identified in thesixth column of this Table (including for example, the actual sequencecontained in an identified BAC clone). In no way is this listing meantto encompass all of the sequences which may be excluded by the generalformula, it is just a representative example. All references availablethrough these accessions are hereby incorporated by reference in theirentirety. TABLE 3 SEQ cDNA ID Contig EST Disclaimer Clone ID NO: X ID:Range of a Range of b Accession Numbers H6BSF56 11 762968 1-591 15-605AW958287, BF027085, AV650800, AV650218, BF689895, BE409727, BE871017,BE278963, BF975253, AA449214, AA150070, BF247445, AA310756, BF337859,AA425098, BE746295, BE732859, BE742068, R48107, BF129114, AA393871,AI707816, AI523073, AW002940, BE672910, BF764476, AW827130, AA468022,AA493695, AW857950, AW275510, AW857971, BF667587, AW021735, R52299,AW965008, AI223604, AI254279, BE179557, BG059450, AW963750, AI445674,AW979031, AV703942, AV762535, AI687343, BG249643, AA769402, AW827120,AA484373, AI345157, AV739452, AW168618, AW504900, AA467876, BF887977,AV710066, AV763354, AV762098, AI744826, BF964993, AA279421, AW302903,AW872575, AI700109, BF437493, AV764329, BE253048, AW270343, AL046205,BE782280, BF677892, AV759437, AV734583, AV760777, AV760486, BF965007,BE907585, AV764578, AW131249, BE297262, BF347740, BF337291, BF679274,AW193265, AI247199, BF347791, AV764307, AV763183, AW235497, AA747070,BF760796, AW872676, AI004704, AW002350, AI270117, AI311927, BF871137,BE883107, AL043009, AI754658, AI250083, AV760258, AW069769, AI370094,AL119691, AW063143, AI270559, AA372481, AV760937, AL119713, AW857949,BF742624, AA720702, BE736829, BF681649, AI953275, AA490183, AF330238,AW970871, AU145314, BF977376, AL138265, AV759172, AV761106, AV735614,AW953071, AA019312, AA584167, AV728425, AU121243, AV763847, AL038799,AV733830, BF965154, BG026806, AI133164, AA523841, AV763540, AV762050,AI470646, AI284640, AI307022, AA635739, AI350211, BE350772, AI691091,AI251082, AI370074, BF936005, AI305766, AI732378, AI860013, AV744393,AW974109, AW500125, AV760378, AV734666, AV764241, AL037683, AL038705,AA683238, BG023888, BC001419.1, AK025830.1, AF151821.1, AC004760.1,AC010679.6, AC005089.2, AC005988.1, AL161908.13, AL049766.14,AC005257.1, AL117377.18, AL109936.10, AC009311.3, AC007383.4,AC018637.3, AL161445.10, AL034545.1, L78833.1, AC023908.6, AC005250.1,AC073964.3, AC006511.5, AC073520.6, AL136223.11, Z95115.1, AC006999.2,AC005606.2, AL022322.1, AC007011.1, AC007279.4, AC007428.5, AP000893.5,AC002476.1, AP002852.3, AC008507.8, AL049795.20, AC016576.7, Z98051.6,AC011508.4, AP003357.2, AL021393.1, AC006285.11, AC005923.2, AL137839.6,AC009309.4, AC003101.1, AL121934.17, AC020893.5, AC004638.1, AP001753.1,AC007620.30, AC010524.6, AF215937.1, AL117332.16, AL022163.1,AC008482.5, AC006077.1, AC022432.4, AC011559.3, AC020658.6, AL161756.6,AC025262.27, AC018711.4, AL121586.31, AC004849.1, AC019215.4,AL357314.11, AC005071.2, AC090959.1, AL391987.15, AL022238.1,AL034423.21, AC006275.1, AL354720.14, AC002314.1, Z82198.2, AC073136.6,AL137780.10, AL358943.13, AC005694.3, AC008744.6, AC010422.7,AL137128.4, AF252830.3, AL135838.5, AL353692.14, AC004686.1,AL121751.12, AC004814.2, AC024084.4, AC005280.3, AL133367.4, AC007192.1,AC002430.1, AL157938.22, AL160471.5, AP001680.1, AL031777.4,AL353748.13, AL021807.2, AL136131.15, AC002395.1, AL136969.7,AL020997.1, AP001646.4, AC018633.2, AC005258.2, AL118501.22, AC018720.5,AL135818.3, AC004008.1, AC006111.3, AL035462.21, AC002470.17,AC016025.12, AC007384.3, AC018712.5, AL136308.4, AC073347.3,AL035667.12, AC004876.2, AC009094.7, AC005020.5, AC002425.1,AL109823.23, AL034420.16, AC007216.2, AC004650.1, AC010465.7,AC006357.5, AL157912.5, AC007225.2, AL078611.1, AF001549.1, Z69706.1,AP001725.1, AL049544.4, AL121892.9, U63630.3, AL499629.1, AC010271.6,AL008725.1, AL021939.1, AL445687.5, AC008670.4, AF254822.1, AC002531.1,AL121601.13, AL022237.1, AC004388.1, AC011310.3, AL450104.14,AC017088.8, AL031311.1, AC005527.3, AL050349.27, Z68162.1, AL121903.13,AC007546.5, AC020917.4, AC025457.5, AL139186.16, Z93241.11, AC015853.8,AC020934.7, AF117829.1, Z82190.1, AC022150.5, AP003471.2, AC013414.7,AL360227.17, AL157931.17, AC004980.4, AL121897.32, AC004622.1, Z83844.5,AC005288.1, AL356481.16, AP001687.1, AL157858.5, AL031286.1, AC022027.5,AC009144.5, AL117258.4, AC005821.1, AC004899.1 AL391839.9, AL356414.11,AP001746.1, AL353668.18, AL365223.19, Z97196.1, AL109921.21, AC012476.8,AF015262.2, AL031662.26, AC016643.6, AC004598.1, AC015555.13, Z83845.14,AL158850.8, AC008372.6, AL080242.11, AL137061.12, AC012309.7,AC004659.1, AL359219.4, AL354707.17, AJ229043.1, AL139113.21,AL590611.7, AL590283.7, AL137853.12, AC008770.6, AF228703.1, AC011477.5,AC020916.7, AC008521.5, AL021578.4, M63796.1, AL009181.1, AC006312.8,AC073657.5, AC024561.4, AC004755.2, AC005488.2, AC005274.1, AC006130.1,AP001721.1, AC022083.6, AC021752.5, AL008712.1, AC004534.1, AC023105.7,AE006462.1, AC006277.1, AL451126.18, AL352978.6, AL133282.15,AC005529.7, AC073138.3, U63312.1, AC016395.4, AC005484.2, AC005531.1,AL033520.16. H6EDM64 12 841331 1-2596 15-2610 AL529288, AL514648,AL523579, AL523918, AL530571, AL528848, AL523917, AL523578, BE795355,BE614208, AL529287, BE797988, BE747962, BE798201, AL530750, BF689293,BE884814, BF508994, BE798313, BE613450, BE787266, AW131835, AL530749,BG248495, BE386285, BF526775, BE873469, BE299650, AL042569, BE621187,BG168950, AW410458, BE883794, BE869375, BF348689, AW239351, BE737181,BE734276, BF309636, BF129214, BG180549, AW410610, AW601905, BE621858,AA689552, BF310547, AW960649, BF953086, AL045821, BE882424, BF724804,BE019151, AW246108, BG179779, AW374338, AW675186, BE279317, BG011956,AI475847, AI394166, AI142042, AW068652, AI539419, AI970048, AI792316,AA536006, AW272491, BG012645, AI827847, BG254459, AI673493, AW007399,AI719374, AA994188, BG176564, AI707847, AW104963, AI220974, AA022523,BF807054, BG012634, BF803094, N24911, AW665019, AI458806, AA689495,AA480131, AI808412, N41812, W17347, BE772562, BG012642, BF807055,BE772573, BG011957, BG012641, AL514647, F22287, AI160580, AI149344,BE772556, AI870582, BE772568, AW801577, BG176616, AW801325, AW068651,AI197831, BE265961, AA483525, BE772566, BE772574, BE693737, AA687509,BE839398, BF799200, AA687451, AI201450, BF896481, BE772569, BE244158,BE772576, BE826728, AI452812, BE772561, AA317941, AA308425, AA745895,AW751437, BG256219, AA782657, BF373198, AA364848, AL039960, AA405870,AW963550, BE300303, N78953, AA112404, BE826586, AI061434, AI143698,AW087863, AI382254, AW731818, BE788591, AW304748, AI589259, AA357514,BF663656, AW673017, AW664622, AA524482, AW246627, BE831243, BE831271,BG055766, AI749023, AA380438, BF746714, BE839346, AW084279, AA113160,BF529848, AI160508, BF764174, BF752908, AA053148, AW842671, F32117,AI190107, BF752929, BE547478, AA977756, AA360528, AA022454, BF808843,BF813892, AI917965, BG011699, BG012316, BF373193, BG122581, AA622680,BF688484, BE772558, AA053706, AA733114, BG012318, AW880294, AA482098,BE256450, BE831281, BF765811, BF803085, BE243388, AA774840, AA576098,BE831236, BE772816, AF024631.2, BC007198.1, BC009285.1, AF096303.1,U73627.1, AF061779.1, AC004923.2, AF238378.3, AC000385.1. H6EEC72 13889401 1-1479 15-1493 BF034355, BF034892, BE792423, BF338898, BG105853,BE390915, BE613966, AA449897, BE389478, AW857371, AW861388, BE891738,R71843, BF983885, BF739366, AI688525, BF591064, AI589048, AI933344,BE387873, AI660119, AI950422, BF830644, AA250941, W68171, BE613313,BE389218, AA699649, BE612723, AI553767, BG178871, BE966158, AW965656,AI807258, AW606086, W67712, N34048, AA789094, AI160489, AA953906,AA029513, AI798377, AA961141, AI191879, AI277742, BF757878, AI341511,BF941471, T79588, W39291, BF843992, BF761673, BE552032, AW938641,AI684229, AI829091, AI696662, H79702, AI803066, AI423727, AW081674,AW014236, AW582288, BE675078, AI760447, BE042621, AA250965, AI991516,AW438983, AW205754, AI658602, AW594379, AA449841, BF926493, AI955308,AI917867, BF063286, AA029448, AI933496, AA350855, R71793, AW578255,BE829073, BE828899, AB014591.1, AL133647.1, AF180474.1, AF211967.1.H6EEU40 14 757048 1-937 15-951 AL534759, AL521087, AL523775, AL518427,AL518354, AL517326, BE741563, BF569745, BF337372, BF570471, BF969174,BG032740, AL536265, BF026597, BE274743, BE546314, AL522079, BE538554,AW960892, BE395781, BE465235, BG167967, BE275462, AI160737, BF804270,BE538514, AA653290, BG163271, AI341701, W94467, AW084148, AI634272,AI634641, AI266283, AI366893, AW409760, AW075307, BF223869, AA604286,AI262840, AA479733, AI985719, W94359, AI271832, AW439127, AI740653,AI500535, AI674680, AW245294, BF032823, BE350203, AI869835, R85540,BF437722, AI394604, AA825592, AW469385, R60570, AI620873, AW470050,AA788601, BE300983, R72347, N77923, AA939017, R72299, R87968, R85120,Z41206, T16501, AA482633, H40664, AA297447, AA081389, R85549, AA558602,AW175922, AA987713, AI628307, AI199953, BG056252, AI382799, AA968853,AA148651, AI289139, AI281228, AA298765, F09249, W94940, AI282067,AI262509, AI200241, AV735503, AI921784, AI628244, T32046, AA302912,AI417848, AI468747, AW055372, AA857797, AA244103, AI581120, AA679586,AI634273, AA694158, AA946762, AA608791, AI124016, H46898, W46963,AA584396, AI797302, AL518355, AL523776, H27881, AL518428, H84434,N99004, AI540357, D31570, BF765616, AA132303, AA814926, BE812370,AW404688, AL532367, AL534760, AA887999, AL530884, AL526404, BE937700,R46056, AL517327, AL536266, R40219, AW468110, H24286, AA522908,AI567331, H26975, T81176, AW369400, T80775, AI952287, AW797699,BE782422, AA872110, BE613072, AW269694, BE870596, AA490287, AI336931,BE937686, BE741460, BE937697, AI910098, AI583322, BE962616, BE932414,AL533205, AI905196, AL521088, AA479862, AK000120.1, AL096714.1,BC007519.1. HACAB68 15 584773 1-1286 15-1300 BF967733, BF340072,AW058572, BE877116, BF029667, BE221318, BE042897, BF434234, BE966145,BF593609, AW966641, BE549675, AI692588, BF433926, W68167, AW674743,W67708, BG163487, AI802057, AW051536, AW005086, BE073104, AU145008,AI634647, AI743810, N51396, BE218196, AI857811, AI816124, AI802067,AI095027, BE503637, BF669349, AI925492, BE669954, AI813855, AI811403,BG236435, AA833834, BE073105, AA748470, AW975666, BE502705, N56917,AI146547, AI949209, AI492350, AI190896, BE219670, AI167132, AW013890,AI089941, AI810922, AI804940, AI689151, BF699838, AW873589, AA209320,N62725, AI420094, AI221693, BF130415, AI301467, AA808217, AW511885,BE073003, AW166094, AA019916, AI359094, BE073109, AI753256, AW675323,BF671156, AA258518, AA954483, AA324329, BF668455, F13496, AA281446,BF247796, AA487161, BF029971, AA730575, AA121642, AI123192, R49582,AI887042, AA487312, AA364288, AA385769, AW440846, R60975, AW451535,AA972339, AI091153, T74984, R36295, AW118180, R75731, BE003024,AI459209, BG055090, AW895451, H80344, AI984894, AA581815, BF877111,AW805837, BE000523, D57701, T03076, AI767454, F10499, Z40296, R43580,AA081798, R49916, BE928534, Z43703, AA493265, AA526871, AU118452,AI144481, BE540542, AL442081.1, AL354793.11, AK001029.1, AF189009.1,AB015344.1, AF293385.1. HACBJ56 16 847112 1-874 15-888 AA157001,BE348653, AW027639, AA534339, AW001883, AA363258, AW959379, T71037,AW953765, BE048583, BF878388, T67200, AW393348, AW393350, AW384705,AW386713, AA156760, AW055343, BF892732, BE140594. HADMB15 17 8471161-316 15-330 AW136268, BG056888, AI131328, AI174443, AI091646, AW117296,AW168872, AI082447, AI432175, AI290911, AI741489, AI682685, AI142536,BG059892, AW149659, AW071935, AA233541, AI183690, BG056462, AI689641,AA599916, BF196591, BF196843, AA199743, AW136277, N77910, AA564806,AA243035, AA779709, AV722133, AI032138, AA844525, AI467910, AW965361,AA852418, AI982751, AI282445, AI982761, T03902, AI420648, AW167499,H08108, BE328548, AW068986, C15651, D52660, AW665899, AI246702,AI538705, AI271662, AI435112, AI288692, BE466948, AI690048, D55112,AA779042, AL536118, D53747, D54101, AA486941, D53384, W07076, AA232504,AA486765, BF832290, AI038647, AW497637, BF947006, AU155428, T05461,AL136582.1, BC001207.1, AB040527.1, AB058762.1, AB040528.1, AB040529.1.HAGFS57 18 847120 1-860 15-874 BF893958, AL079477, BE221875, AL532698,AI299412, R51649, AL040440, AA339493, F12505, F05649, Z43527, F06606,R12847, BF690787, R25251, T74335, AW382934, AB020663.1. HAGHN57 19773286 1-2426 15-2440 AL533248, AU118622, AU119331, AU133909, AU119469,AU118182, BE794468, BE791529, BG176702, BE280450, BE729801, BF663566,BF970116, BE257176, BG032912, AL516224, BG121097, BE784191, BG249033,BE727671, BE881192, BE745390, BF792305, BF037862, AV710149, BE617085,AV751361, AW291174, BG163346, AI686123, BG033409, AV762315, AV704873,BE540243, BF344980, AV707943, BF671351, BE394881, AW070780, BE538770,BF303671, BE541947, AW963773, BF303913, AW299817, BE378370, AW299807,BF107096, AW515893, AI338838, BE254836, AW402330, AA455894, AI436127,AL516223, BF001973, AI392820, W31025, W28207, BE535313, BE258523,BF109189, AA182513, BE617702, AW275883, AW674662, BG169977, BE711218,AA134574, AW304388, AA588768, BE868534, AU144819, AA455892, BF802948,BF222585, AW902162, H16095, AI034153, AU145137, AI905391, AI985354,BG011776, AW612879, BE711276, AV659416, AU150558, BE702340, BF055535,BE711244, AA652292, AW271981, AA780056, AI624858, AA319693, AA604113,AV744893, AW771218, AV742941, AA837954, T60588, AA150957, AA151047,AI991761, AI912891, AI628783, AI434787, AW072744, AA716130, BF807693,AA181782, AI554969, AA916968, AA101864, AI473865, AA362607, AW338509,AI525459, BE244147, AI928082, AI433249, BF062859, AI910904, AA285264,BE711295, AI354885, AW006732, AI950274, AU144122, AI990867, AI922170,AA115829, AA806393, BE672240, AU156842, BE243206, AI633602, W01852,BE711219, AI280611, AA707161, AA301320, BF197637, AI695111, AW966603,BF447153, F29695, BE378061, AA336840, AI424341, AA385049, AI307649,N58884, AA131117, AI205138, BF431130, BF807685, N98771, AA602492,BE711204, BF438567, F34557, AA748737, T60437, AA745028, AW891490,AW673414, AI630237, AW378199, AW779341, BE172988, BE172375, AA101187,AA781579, AI478435, BE699167, R57333, AI927982, R92570, BE764834,BF818234, AA648053, BE464290, AK000994.1, AC004668.1, AL050216.1,AA227675. HAJAA47 20 534670 1-1223 15-1237 BF991208, BF743765, AW021917,T74524, T57767, AI491765, N22058, AA904275, AA228349, AI689019,AA054085, AU131834, BE256101, AW270771, AL119691, AI284543, AU118852,BE062478, AI859946, BF769528, AW873261, AW152178, AC009318.11,AL161656.20, AC011811.42, AC018462.4, AL023799.5, AC012170.6,AL137796.6, AP000704.2, AL499628.1, AC007934.7, AC005082.3, AC006111.3,AP001711.1, U91323.1, AC002407.1, AL031680.20, AL356244.12, AL391280.15,AC008526.5, AE006639.1, AC009131.6, AL132987.4, AP000103.1, AL158207.15,AL049540.11, AC013434.8, AP000269.1, AC008755.6, AC008592.4,AL355336.15, AK024933.1, AC090518.2, AE006640.1, AP000212.1, AL133211.9,AC008924.5, AL035422.12, AP000280.2, AC011471.6, AC018719.4, AC005200.1,AC005000.2, AC017079.5, AC004858.2, AL133163.2, AC011472.7, AC009488.5,AF045555.1, AC009756.9, AC007546.5, Z98044.13, AP000107.1, AC008267.6,AC005520.2, Z98050.1, AL121933.15, AC002994.2, AC009137.6, AL133174.15,U47924.1, AP000031.1, AP000354.1, AC011224.8, AL162430.15, AC008450.5,AL021154.1, AC011449.6, AP000039.1, AC000025.2, AC004526.1, AP000355.1,AL356057.12, AL137798.8, AC012085.4, AC004383.1, AC004998.2,AL049713.20, AC005077.5, AC011485.6, AC004253.1, AL449209.2, AP000065.1,AP000134.1, AC008521.5, AP000446.5, AC004477.1, AC022173.7, AL356915.19,AL031432.1, AC026172.3, AP001727.1, AL139415.10, AC012351.3, AC011442.5,AC009412.6, AC005920.1, AL157858.5, AC010271.6, AC010636.6, AL513550.9,AL009183.10, AC020983.7, AL109811.39, AL109797.18, AL022237.1,AC069262.24, AC024078.4, AC004232.1, AC007371.16, AL157882.5,AC011470.5, AC008753.8, AL590762.1, AC005484.2, AF109907.1, AC009155.3,AC004882.2, AL109827.8, AC011452.6, AL121891.22, AL109804.41,AC011465.4, U63721.1, AL357515.26, AL512347.14, AC008738.6, Z81364.1,AC025280.4, AL138878.10, AL050308.9, AL117380.28, AP000471.2,AC002487.1, AL161659.17, AC008764.7, AC005480.3, AC005841.3, AC003070.1,AL022163.1, AJ224877.1, Z93017.6, AC005220.1, AC004821.3, AC005755.1,AC005944.1, AC010319.7, AF157623.1, AJ012824.1, AL353701.15, AL135783.6,AL359236.4, AL122020.5, AL133264.10, AC007366.4, AP001714.1, AL352979.4,U62293.1, AC003959.1, AL359092.14, AC008403.6, AC004968.1, AC011475.6,AC008747.5, AC005409.1, AC027644.9, AC020916.7, AL139353.3, AP001752.1,AL160397.17, AL022312.7, AC005231.2, AC020904.6, AC018663.3, AC010170.3,AL356378.17, AL137073.13, AC005288.1, AL049872.3, AL133405.17,AC008249.14, AC002389.1, AC002492.1, AL139405.11, AL136126.34,AL009179.1, AC073517.5, AC007057.3, AC013356.8, AL137852.15,AL138707.10, AL049775.2, AL135744.4, AC011816.17, AL135752.6,AC007345.5, AC073073.2, AL034402.9, AL160175.5, AJ277546.2, AC020552.4,AC011742.3, AL353777.18, AC008805.7, AL139317.5, AC002301.1, AC010458.5,AC009965.9, AP001719.1, Z98200.8, AC007163.3, AP000167.1, AP000052.1,AC072052.6, Y15994.1, AC002430.1, AL021940.1, Z98752.16. HAJAY92 21845601 1-2331 15-2345 AI208943. HAJBV67 22 866415 1-2522 15-2536BG252656, BF732416, AV713753, BE905485, BF062374, BF445098, BF110352,BG252894, BE620095, BG249923, BE867752, AW606977, BG171028, AW576585,BE868698, BF671587, AW860769, BF941584, BF986308, AW305358, BF037687,BE541890, AW958924, AW974216, BF105260, AL048954, BF434917, AA057428,AW860733, BF664978, AI040432, BF984881, BF114918, BE872774, BE349491,AW263003, BF697715, BF382321, BE938703, AI378631, BF447674, AA446149,AA044378, BG114831, BF815345, BF085497, BF815237, BF210190, AA579908,BF132467, AA437015, AW860753, AI741531, AI742016, AI963805, AV748930,AA457625, BF815346, N31845, AI927889, BF699623, AA587067, AA831367,AI038411, AA442844, AI382172, BF084350, AW993684, AW407667, BF029928,AW028681, BE327066, BF887305, AV695738, BE222425, AV696527, BF755168,BE876090, BE167030, AI768063, BE000825, H12700, AV708152, AW001069,H03274, BF063098, BE933732, BF815719, BF594797, AW974217, N93209,N23944, AI290752, BF802746, AA557778, AA604449, Z32781, BE004621,AA910221, AA226865, R78864, BF326913, BG179582, AI370350, BE719765,BE768063, BE932712, AA780882, T31498, AW798498, AI635435, BF088211,BF817478, Z28655, BF943308, Z24930, BE932705, BF126152, AI015125,BF981166, AI684725, T36185, H12701, R37535, AW952059, AI689130,AA296931, AW798657, AW364905, R79351, H03275, BE768230, AW206046,AA081583, AA936681, BG104571, BE176285, AW993023, W69607, R31681,AI479514, BE696398, AA716370, BE463676, AW366456, BE869217, BF064127,BF001446, AW884802, AW999085, BG104993, AI039088, R31723, AW366514,BE871677, AI241206, AI743907, AA306185, BF037794, D61175, AA852523,AW365573, BF799275, AA129989, BF985004, AW838470, BF802748, R36687,BE001097, AA723997, BE932064, AW366145, BF230069, AW999007, AW993306,BF733961, AA508532, AW972441, AW972636, BE932056, BE086739, AA164808,BE064535, BF986296, BF095055, AW408116, BE184804, BE184805, BE184738,BE695142, BE184803, BE172976, BE184743, BF984676, BE184732, BF741954,AI366900, AW082623, AW118518, AI698391, BF871314, AI954504, BF753053,AI679312, BE967260, BF207979, AL515195, AW050850, AW089844, AW151136,AL515191, BE965599, AI619607, AI687568, AI540674, AI345688, AL513817,AI590043, BG032036, AA806028, AL043168, AA329665, AI923989, AI670002,AA641818, AI866770, AI679321, AI591420, AI473451, AI445165, AW051088,BF812961, AL514093, AI521560, AI633125, AL514871, AI915291, AW152182,AI247082, AI582932, AI889189, AI587121, BE875959, AA743012, BF814412,AW193894, AL515413, BF911554, AI918449, AF269150.1, AK027788.1,AK000756.1, AF116347.1, AK027438.1, AF160213.1, AF124819.1, BC009311.1,BC001967.1, AB048975.1, AL137478.1, BC002733.1, AB056421.1, AL133560.1,AK027129.1, U42766.1, AL08118.1, BC001969.1, AK026927.1, U38847.1,AB047878.1, AK025857.1, BC004264.1, BC004899.1, AL137529.1, AK000323.1,BC005858.1, M92439.1, AL122100.1, BC006458.1, BC001964.1, AL353956.1,AL137557.1, AF132676.1, AL133640.1, AF061836.1, AL137533.1, AK027164.1,AJ406939.1, AL049430.1, AB056427.1, AK027173.1, BC007571.1, BC003122.1,AL136784.1, AF245044.1, BC001215.1, BC004324.1, AF252872.1, AL389935.1,AL136752.1, BC003410.1, AL137560.1, BC008037.1, AL137555.1, AK026649.1,AL136767.1, AK000206.1, BC003658.1, AK026057.1, BC008284.1, AL136786.1,AL110225.1, AL133623.1, AF078844.1, AF353396.1, AB050407.1, AL049938.1,BC007391.1, AF090903.1, AL136747.1, AL050138.1, AL137550.1, D83032.1,BC007053.1, AL512704.1, AK027113.1, AK024588.1, BC001774.1, AL137258.1,AL390184.1, AK000310.1, AL096744.1, BC006136.1, AB060914.1, Y16645.1,BC003619.1, BC008781.1, AL389939.1, AF028823.2, AL110196.1, AK025435.1,AB046642.1, AB050431.1, AK024944.1, AK000414.1, BC000054.1, AB052191.1,AL117435.1, AL110218.1, AK026534.1, BC008780.1, AL136622.1, AL049283.1,BC002697.1, AF069506.1, AF141289.1, BC004958.1, AB063079.1, BC003548.1,BC001056.1, AK025113.1, AJ010277.1, S76508.1, AK000160.1, U72621.3,AK026857.1, AK027096.1, BC003614.1, AL137271.1, AL137459.1, AB063088.1,S77771.1, AF036268.1, BC004556.1, AL157433.1, AK024622.1, AB049852.1,BC004292.1, AK027082.1, AK026749.1, AB063093.1, AB044547.1, BC008078.1,AL110224.1, BC009294.1, BC001082.1, AK027111.1, AL157482.1, AL122104.1,AB050410.1, BC000714.1, AB063087.1, AL080140.1 AL442082.1 AL137488.1AF056191.1, AK025465.1, AL122050.1, AL133606.1, AL136882.1, AL133559.1,AC008250.23, BC000725.1, AK027116.1, AK026547.1, AK027121.1, BC007456.1,AF232009.1, AB055352.1, AB056420.1, AL136644.1, BC006525.1, AK025312.1,AL133016.1, AL080074.1, AL512765.1, AL359620.1, BC001844.1, AY026527.1,AL050172.1, BC007499.1, AK026462.1, AL117635.1, AK027114.1, BC003104.1,AL050277.1, BC006091.1, BC008899.1, AB060879.1, AK026959.1, AK000083.1,AK027160.1, AK000618.1, BC007420.1, AL133568.1, AL050393.1, AF227198.1,AK000653.1, AL049347.1, AL162002.1, AL137480.1, AL162079.1, AB062942.1,AL390154.1, AB060897.1, AL110296.1, AL136893.1, AL080148.1, AL122121.1,AL133112.1, AK026593.1, AB049892.1, AL122110.1, AK026542.1, AF100781.1,BC005825.1, AK024992.1, AK026894.1, AL512684.1, X83544.1, BC004290.1,AK026541.1, AF183393.1, AL512746.1, AB051158.1, AF106697.1, AB063071.1,AK000421.1, BC003590.1, AK000257.1, AB060917.1, AF090900.1, BC007680.1,AK027188.1, AL023657.1, AL137292.1, AL133637.1, AL049324.1, S78453.1,BC008416.1, BC008836.1, AJ299431.1, AB047941.1, BC007460.1, AK026613.1,U55017.1, X67688.1, BC004336.1, AL390139.1, AL110221.1, AF262032.1,BC003602.1, BC002476.1, AL110222.1, AL137521.1, BC006181.1, AL137479.1,BC006807.1. HATCD80 23 826098 1-1795 15-1809 AW936395, AA382841,BF380111. HATEH20 24 836056 1-836 15-850 AW978851, AI686323, AI767653,AV747166, AA829515, BF512171, AA034240, AA053933, AA737691, AA533167,AW261869, AA835698, AA447216, AI623248, W92607, AA835700, Z21891,AA599963, AW893940, W95232, T20153, T20152, R57454, AC006207.5,AB020865.1. HBAGD86 25 838799 1-1699 15-1713 AI658681, BE466145,AI806836, AI653272, AA004211, BE302094, BF970406, BE018485, AA418617,AA594901, AI580148, BF589715, AI804211, AI669907, AI342168, AI810310,AA506350, AW022528, H10330, AA721162, AA452114, W03931, AW953290,AI262137, R61309, AA680147, N62384, H10331, AI264925, AA765972,BF086698, AW275301, AA485210, C15277, N79353, AA350799, AI867727,AI474438, AI129224, AA093047, D60782, AI535847, AA897480, AA350798,AV714899, AW956763, AV728867. HBGBC29 26 691473 1-1842 15-1856 BF223021,BF036281, AI341667, AA180986, AU153625, AU151704, AI093197, BE855464,BE018834, BE616741, BF684563, AI694268, AA031711, AI469856, N63041,N50125, AI150599, AI597740, AI985206, AI671591, W72535, BF431270,AI741942, AA037642, AA180865, AA031648, AA436065, AI800796, AA129939,BF056140, AW002265, AU157670, AI074205, AA830493, BF063800, AI056532,AI656721, W00519, AI275143, AI337739, AW172525, AA443349, AA043021,AA446926, AI655558, AI769027, AA101851, AA917703, W93307, AA526333,AI689128, AA777090, AW002829, BE295568, AW139517, AI128702, AI276137,AW801873, AA873711, AW892754, N98234, W76109, AI631104, AA856832,W92810, AA042939, H87505, AA129938, AI688779, AA693329, AI676108,T87624, AA570072, AA037641, AI186390, AW515672, AA031685, AA037500,R82703, AA037234, AW380430, AA985191, AU131994, BE302396, H87506,AA938640, AI926907, AU118291, AI696069, T74071, AA102060, AW057528,AI671894, AI962374, AI695458, AA046964, BE869607, BF814627, F12449,AA725452, AI968837, AA917824, AA054749, BF437316, F10070, AA917678,BE218382, BE669660, AI916503, AW612381, AA683581, AI984598, AA937814,AI932475, AA046963, AA053281, AI801723, BE858841, AI499751, AA031686,AI074981, AI341558, AI478279, BF735972, AK001006.1, BC004523.1,AF020920.1, AF038662.1, AB024436.1, AF022367.1. HBGNC72 27 892131 1-78815-802 AL526130, AL524570, AW003889, AI935768, AW440485, AI936267,AA713525, AW272919, AI796977, AI951842, AW014081, AI760160, BF941209,AI263194, BF475772, AA496533, AW514179, AA724851, AA496454, AI799782,BF589971, AA496526, BE646016, BE563432, H41355, AW264331, AA515579,AI582716, AI581108, AI208124, AA927044, AI695535, AI638313, BG170255,AI147521, AA199585, AW264237, AW248758, AB033019.1. HBHAA05 28 6031741-676 15-690 AI572680, AW631267, BF970107, AA632355, AI433952, AI753969,AA629668, AA493546, AU158457, BF589864, AL044966, AW518882, AI570067,AI828721, BF028225, M77888, AI884404, AI547110, BF724416, AI434103,AV683406, AW836225, BE391183, N55076, AA610644, AV731938, AA313025,AA748071, AV743067, AI065031, AW148964, AI280566, AI732690, AA601376,AI311796, AI268465, T03928, AU158814, AW504667, AW880986, AI819419,AA018258, AA524800, AW971342, AI791659, AW020612, AV759022, AV712092,AA935827, AA773560, AA425283, AI376687, AA493245, AA847341, BF942991,BF944618, AW303052, AI174703, BE392753, BG034698, BG223498, BE152006,AI683079, AA826166, AI590404, AI285651, AC004531.1, AL049780.4,AC006013.3, AC005971.5, AC005522.2, AL138713.11, AC011445.6, AC008403.6,AP001725.1, AC010458.5, AC009412.6, AP001726.1, AP001715.1, AL022323.7,AC008569.6, AL138976.5, AC005015.2, AC005081.3, AL022316.2, AC008738.6,AL590762.1, AL445222.9, AC004967.3, AC004991.1, AC020552.4, AP001716.1,AL109965.34, AC006211.1, AC011514.3, AC011485.6, AJ003147.1, AC018755.3,AC011510.7, AC006057.5, AC016995.4, AL353692.14, AC006334.3, Z97054.1,AC006449.19, AC005940.3, AC004383.1, AL034422.24, AC087071.2,AL133229.40, AL079342.17, AC004051.1, AL359397.3, AC018719.4,AP001712.1, AP001724.1, AC020716.3, AC073316.6, AC024561.4, AC010422.7,AC009488.5, AC020908.6, AC000353.27, AL513366.11, AC006487.8,AC020906.6, AC008066.4, AL354735.14, AC006530.4, U95742.1, AL162426.20,AC007731.14, AP000289.1, AL389925.10, AC005500.2, AC002527.1,AP000042.1, AP000110.1, AF001549.1, AL135905.6, AC007637.9, AL161732.7,AC067941.7, Z98941.1, AC032011.14, AP000688.1, AC005377.2, AL050335.32,AC090937.1, AC007256.5, AF053356.1, AC079602.15, AC008623.4, AL163032.3,AC011490.7, AC006040.3, AC004821.3, AC007216.2, AC005881.3, AL133545.10,AC008891.7, AL109825.23, AL138756.23, AL355102.5, AC004703.1,AF312032.1, AL445664.14, AL354696.11, AC005529.7, AC005077.5,AL158207.15, AF168787.1, AC003982.1, AC013449.8, AC021019.5, AC005914.1,AC004032.7, AL158052.10, AL353752.6, AB003151.1, AC005052.2, AC005291.1,AC004867.5, AL023583.25, AC020931.5, AC008752.6, AL023693.25,AC004887.2, AL078639.5, AL031651.33, AC005098.2, AC008551.5,AL136304.10, AL023807.6, AL356756.4, AC005921.3, AC005874.3, AF134471.1,AP001714.1, AC004906.3, AP001748.1, AC004166.12, AC020744.4,AL031118.21, AL139109.14, AC011895.4, AC006312.8, AL049537.48,AC007374.6, AP001630.1, AC007383.4, AC010616.5, AL109797.18, AC006970.6,AC005399.19, AC018711.4, AL020997.1, AC087311.22, AC005632.2,AC005578.1, AC018462.4, AC004522.1, AF243527.1, AC010605.4, AP000563.1,AC026464.6, AP003476.2, AC006511.5, AC004796.2, AC004000.1, AL356113.8,AC011005.7, AP001711.1, AC008857.5, AL138885.21, AC010319.7, AC073347.3,AC002472.6, U52112.1, AP000211.1, AP000133.1, AC009131.6, AC074121.16,AC004263.1, AL449223.7, AJ400877.1, AL161670.4, AC008812.7, AL445071.14,AL117336.22, AC007298.17, AL139343.9, AF207550.1, AL359092.14,AC004963.2, AL096840.25, AC012170.6, AC025593.5, AC022384.4,AL035089.21, AC008969.5, AL355512.22, AP001646.4, AC073542.4,AL359382.23, AC011495.6, AC005562.1, AC002565.1, AL034449.1,AL034549.19, AC008892.5, Z98200.8, AC005102.1, AC012450.9, AC006538.1,AL445483.13, AL354720.14, AC069285.8, AL034548.25, AC002432.1,AC008982.5, AC025166.7, AC005618.1, AL109804.41, AC012085.4, AC008481.7,AC020913.6, AC022432.4, AC005520.2, AC005627.2, AL021395.16,AL117380.28, AC008543.7, AL158824.11, AL109935.39, AL161802.15. HBHAA8129 846465 1-1633 15-1647 AL138080, AL138081, BG056111, AW117532,AI885223, BF724275, AW051808, AI332809, AI564820, N63569, AW207494,AI866785, AW148811, AI954565, AI199326, AI199105, N38888, AI243422,H09138, AI986175, AW381536, Z25110, AI991904, Z18300, F31192, Z28916,AW381528, Z41646, AI954371, N38887, AI033629, Z28784, AW381480, N94825,F25740, F00372, AW380848, F16581, AW381481, AA197180, AW104762,BF887537, AB042554.1, AB032999.1, AC006059.3. HBIAC29 30 831751 1-176815-1782 BE792362, AU119261, AU117435, AU135719, AL522995, AL523062,AV725708, BG257393, AI033807, AL524959, BG258772, BE005784, BF105898,AW157169, AV695633, AI707987, BF965323, BF794704, BG112387, AA877792,AV697750, AU145651, BE268042, AA001404, AI401215, BE568337, AI812036,AW161740, AA428415, AW182986, AI275437, AW160483, AA678033, AI051135,N40528, AI864046, AI292230, BF670616, AA586803, BE564896, AW294845,AA134820, BF245314, AA768585, BF680744, AI816108, AW163143, BF219379,AW161133, AA506157, AA492248, AI298933, AA594861, AA013286, BE673778,AI421629, AA018334, AA905534, AI684501, AA427401, AA082812, BE768733,AA287601, AW157614, BE768540, D79434, BF946436, AI658777, BF541249,AV696430, AA287752, H98178, BF540910, D79454, D79495, AA018335,AV692094, R11115, H98502, BE768718, D79471, BE768713, AV692366,AV694591, AA808656, BE768500, D62307, R84940, AA037183, AA804276,D79442, AA284650, T93079, N46576, D62351, D62288, AV696341, AW440057,D62360, AW163531, AI057422, D79425, R11059, AA359531, AU156237, W27841,AA013043, AA323139, BF219327, AI991658, D79500, AW613472, BE768582,D61951, T93170, AL524958, BE544935, D62369, AV657638, D62200, AI702248,BF948281, AA134819, D62264, D79447, AV656951, D79470, BE043970, D62243,AA934540, N67412, AW118285, AA483825, D62298, AI911842, AI033466,R31032, X93846, D79508, AI371542, R31522, D79465, AW590942, AW466905,AA180979, AA059251, AI689493, AW661808, AW006273, D63025, AW449881,AI866210, AA059003, N71916, AA381297, AW873906, AW590669, N55843,D79405, AW169134, BE390691, AA585262, AI754249, BE389098, AA059266,AI459286, AI991649, N84299, AI655153, BE548704, AW016856, AI400471,AI400469, BF218780, AY007166.1, AL034379.8, AK021792.1. HBJAB02 31837309 1-1679 15-1693 AL529646, AL529645, BE898304, BG112747, BF791411,BG036058, BE392384, BE621757, BE548173, BE895853, BG034671, AA808894,BE901085, BE278873, AW152607, BE795658, AW166898, BG122141, BE782474,BF972826, BE793716, BE140314, AW750993, AA826362, AW517942, BE714673,T59668, BE731030, BF939314, BE732766, BE745104, AI290469, BF477770,AI805651, AI961329, AA581089, BE902575, AW197375, AA974066, AI950259,BF802171, W27729, AV693783, AA877530, AA715365, AI968889, AA885542,AA160748, AA386371, AA335719, BF873961, W73105, BF223151, BE740826,AL120854, BE548914, AA318192, AA501478, BF125073, AI948815, AA581100,AA658457, AI621069, T59802, AA468534, AA503715, BF850755, AW956069,AW841506, AI144504, AA352215, BE897964, BF883404, BF373009, BE090290,BE168997, AW855521, AW820855, BG230749, BF376598, BE622839, AV699089,AV647789, AI567702, AV726156, AW961037, AW411235, AV726058, AW020397,AV706279, AV702427, AV651955, AV702026, BE393551, AV727787, AV660608,AV687176, AW021717, AV698545, AV687909, AV709256, AV708438, AV656903,AV661704, AV696106, AV697196, AW409775, AW951263, AV689111, AV655280,AV728157, AV692345, AV659322, AV654908, AV656478, AV708893, AV709314,AV708381, AV660728, BG168549, AV659536, AV691080, AV706219, AV695545,AV652001, AV705159, AV648263, AV703169, AV728518, AV707541, AW952409,AV709660, AV726624, AV706854, AV729220, AV709604, AV687035, AV696866,AV728997, AV704955, AV726816, AV725920, AV652156, AV701707, AV656283,AV704234, AV708025, AV707933, AV684604, AV729378, AV708980, AV692691,AV701914, AV708723, AV702516, AV693523, AV709407, AV705693, AV708992,AV729263, AV726103, AV708704, AV727029, AV726520, AV728733, AV725826,AV702021, AV725134, AV705280, AV645906, AV683415, AW265004, AW964228,BE047925, AV705076, AV707792, AV729259, AA127565, AW022102, AV686064,AV701067, AV704124, BC000131.1, AK000069.1, AC015651.18, AF147378.1,AK027463.1, AF097996.1, AF217986.1, AF217994.1, BC000090.1, BC003658.1,BC008282.1, AL356376.9, S71381.1, AK026494.1, BC006378.1, BC004362.1,AL137283.1, AK000212.1, AY026527.1, Y08991.1, BC007199.1, AF218004.1.HBJAC40 32 841235 1-1753 15-1767 BF345048, AW958511, BF530417, BF975837,BE253816, BG250686, BE887472, BF527935, BE263703, BE909332, BF527878,BE881895, BF194837, BF972454, AW025541, AL048612, BF525861, AI859062,BF835934, AI199762, BF955165, AI052782, H12219, BF955173, AW015231,BE379375, AI681619, BF364391, AI379848, AI363268, BF740272, AA703554,R60286, BF955168, R52740, BE258881, AA448130, R90880, W46453, BF090044,R25794, R22673, R52690, H08245, H08001, AA447988, AA912056, AI245669,R36729, AI290546, H07130, M78974, BE179040, T77037, AA070715, H08144,R58852, H38448, Z44633, H49103, W46520, R09542, R85342, AI879032,AI590525, R43378, R90851, T31004, R67310, F13258, BE164925, AA364956,F08103, T32340, BE907755, Z40495, C03430, BF884758, R85671, T35911,T30880, F28188, BF115735, AW161049, AW072139, BF820428, R60889, R60792,AA694126, AI086328, BF961135, AI272235, BE258962, AI363035, F04345,R46793, AA095937, BF952087, F10861, H06622, BF841177, BF925698,AA401578, BF820431, BF945162, BF772214, AA095307, R54673, BE677392,AW027215, AI360330, AF072812, T16940, AL035745, R09655, BF945153,BE081049, BE179106, AA382430, W23297, AW162615, AA946598, AI017807,AI220189, AW002147, R85343, H41244, BF527814, AI863690, AA394215,AW961330, AV652536, AV652547, AW963011, AV654689, AW954779, AW958365,AW954506, AV708498, AW957970, AW950179, AW963847, AV709494, AV725063,AV706850, AV725970, AF131218.1, BC002882.1, AL136698.1, AF195661.1,BC007604.1. HBJCR46 33 815649 1-3194 15-3208 BF980168, BF001800,BF221545, BE180558, BG117357, BG165887, BE747286, BE867206, BE559905,BF029089, BE884542, BE180560, BE882087, BF672818, BE180608, BG255311,BF695020, AI765879, AV701340, AI832097, AV701354, BG164080, BE568492,BF979546, BE268392, BE180559, AI927915, AI675415, BF195785, BF662916,BE673547, AI086866, AI956035, BF671543, AU146956, AA479515, BF063974,W19888, AW992096, BE504075, AW069858, AW992159, AA626631, BE019647,BE221636, AA479513, BF575729, AU144777, AA973047, AA936602, BF671187,BE545703, AV701112, AU144811, AU160319, AI472144, AI263407, BE019684,AU118130, AW614133, AI954073, AI767153, BF445898, AW087744, AI913738,BE397963, AI628089, AI675273, AA447852, AI635143, AW129685, AI287605,AA486193, W00613, AW135604, AI754985, AI334344, BF062454, AW119185,AW576204, BE041839, N54388, BF354864, AI275063, BE175440, AA883965,AI554276, AI082201, BE718001, AW771023, AI274243, AW337565, AA150018,BE175441, AW771580, AA447700, AW052155, AW771203, AA085991, AA085621,AI954014, AW068250, BF725222, AA486299, BF087209, BF834780, AA971016,AW854246, AA150083, H08089, BF735392, BE180609, AV683146, AA677738,AI220075, AV701437, AA740363, AA909807, H71626, R61225, N49411,AV689665, C05160, AA888983, AI026772, AV692963, AW580238, AI816858,AA340276, BE180555, AW862217, R61226, H82142, AW068158, H08090,BF997557, AW862230, AI565387, AI824475, T32511, BE169765, BE002988,AI004624, AW514293, AA775740, T31977, AI660017, AA347780, N63302,AW468684, AA908821, AA953180, AA897589, AI217393, AI536640, AA337664,BF364138, BE816022, AA652646, Z19403, C04239, H71627, AA347779, R14260,AW168255, BF833756, Z42097, AV655482, AI431630, BE088874, BF348891,H82048, AA130053, AA781872, BE544862, Z28501, AI434730, BF575085,AA328725, BF084834, R96217, AU155530, Z38367, AA301061, AA370106,AI810366, AW836437, AA371349, AI991790, H54404, AW015692, Z42140,AI905103, AW242449, BF327421, AI824674, AW195816, BE173133, BF812520,R86231, AI274472, H54488, AW379997, BF476783, D62662, AA382472,AW379945, AL079373, AA703490, AW381290, BF328480, AW392784, AI823416,BF961200, BF910517, BE728262, BE408949, BE277648, AA458950, BF797287,BE866243, AA923063, Z24943, AA236098, BE160734, AA397692, C02287,BF812876, BF444939, AF150734.1, AL136738.1, AK000984.1, AF124434.1,AL033531.10, AL031287.3, AL033532.36, Z97876.1, AC007034.4, AL035304.1.HBJDW56 34 520401 1-623 15-637 AC005532.1, AL031319.5, AL354933.8.HBJEL16 35 847030 1-736 15-750 AI279501, BE867835, AL528252, AA569392,AW856935, AA071326, AA587712, AA258409, AI341817, BE898008, BE696253,AW576885, AA837880, AW576895, AI584147, AL525748, AW383278, AA071368,BF330803, AW383120, AI393286, AL513864, C00710, AW857093, AA644480,AL528253, AW499908, BF326342, AW749039, BF771813, AA193585, AW383268,BG031591, AL040224, AW383242, BE904616, AW751656, AW383266, AW383144,R15553, AW383205, AW383131, BF931485, AA258753, AW383275, AW383146,AW886371, AW997055, AW996855, BE929916, BE005368, AA188924, BF350669,BF327032, Z99943.1, BC007881.1, AL035308.1, AF087020.1, AL035302.1,AF092425.1, AF095727.1, AF092424.1, AF239756.1. HBJKD16 36 853358 1-161515-1629 BG259133, BG258754, BE895955, BE535182, AU119776, BE296370,AW361272, AA205862, BE079707, AI743764, BF669591, BF102652, AA768863,AA767455, AA683506, BF374311, W39021, AA583062, W94893, BE737722,AI128320, AA703242, AA402965, H12229, AA027163, AI338954, W92057,AA769377, AA811137, AW470052, AA027162, AV713020, AI680487, R19758,AA283191, AA531492, AI700367, BF946853, AW514119, AA644413, AI004120,AW876599, BE868122, AI831977, AI219655, AA197283, H17722, AA890197,N70828, AA164346, AV750338, BF791719, AA164345, AA767095, AA393969,AA765421, H17611, BF247968, AI254347, AA253013, AA534905, AA470446,AA182675, H12230, H43795, T32973, AW386765, AU146033, AA078964, R51414,AI269757, T33350, R45177, AI203452, Z44609, AI041094, AV749975, H43709,BF336945, AI268058, T30703, R85203, R51302, R51996, BE738484, W84649,R51995, AA824604, W01425, AA907096, BF801374, BE544754, AI469616,AU156273, AW297202, T83337, H14279, BE929477, AA252973, BE242053,T18899, AA248529, H14306, BE698663, T33352, BG059012, AA361817,AA236020, AA810717, BE243263, AA876139, BF240162, BF893858, BE217859,F13420, H53830, F08935, AA078866, AV727864, AA721692, Z40480, AI383780,H52715, H48241, AW751348, T83485, AI567913, AI247225, BE694869,BE940539, BE713625, BF858355, BF801742, BF824816, BE713728, BE713771,BE713469, AA463921, C01352, AW608887, BE714022, AW876620, AW876628,N89830, BE002346, AA192537, AA319174, BE714013, AV709029, AW991462,AI080442, BF993596, N57976, AA034034, BF799178, BF818732, AW392976,AW876544, BE568245, AW835734, AK000087.1, AK021899.1, AF217983.1,AC008074.3, AK024658.1. HBMBM96 37 561935 1-1062 15-1076 AI888795,AA047754, AI561027, BF676343, AA047704, AI187148, AA314069, AA536040,AW976024, AA704393, AI754653, BE973547, AV762633, BF857849, BE897079,AU144320, BF681619, AV757032, AW972919, AW819125, AW151824, AV763457,BF854308, AI306232, AI251576, AA904211, BF589788, AA812058, BE245576,AL042667, AL042670, AI521525, AI891080, AW961593, AI583466, AW274191,BE878926, AW020150, AI459904, T74524, AI280266, AI459943, AA653139,AW572721, F16345, AV729669, AA515728, BF805088, BE350953, AI601229,AA297802, AA747757, AA297145, AI926102, AA629540, AI436433, AI679221,AA084609, BF724838, AW270385, AA164955, H59737, BG029528, AI473995,AI340641, AW504667, AW969831, AA805049, AI858691, AI749893, H07953,AC000057.1, AC008891.7, AC011484.4, AC005920.1, AC005225.2, AC006011.2,AC006126.1, AC005837.1, AL031658.11, AL109825.23, AC005940.3,AC018828.3, AE000658.1, AC008481.7, AC022383.3, AC022425.6, AL109804.41,AL049766.14, AC022384.4, AC004089.25, AC002352.1, AC005015.2,AL512378.7, AC004797.1, Z93930.10, AC009756.9, AC008397.7, AP001711.1,AL035422.12, AL135838.5, AC005519.3, AC008403.6, AL109935.39,AC004878.2, AL590763.1, AC005696.1, AL159977.10, AP001725.1, AC009131.6,AL121983.13, AC005907.1, AC009060.7, AL353807.18, AF111169.2,AC005231.2, AL121972.17, AL049760.26, AL354932.26, AP000547.1,AC002425.1, AC005544.1, AC011442.5, AL031228.1, AC004526.1, AF243527.1,AC005081.3, AL035681.13, AC005291.1, AC009309.4, AC008440.8,AC032011.14, AL139113.21, AL139022.4, AF196972.1, AC004019.20,AC020550.4, AC003982.1, AC009077.7, AL034423.21, AL031311.1, AC000025.2,AC007664.12, Z93241.11, AC009032.7, AC005944.1, AC002039.1, AC003690.1,AC005756.1, AC011247.10, AF196779.1, AC008760.6, AC008265.15,AJ295844.1, AC004150.8, AL162426.20, Z99716.4, AC011472.7, AC011461.4,AC022392.4, AC005399.19, AL353194.13, AC011005.7, AC011895.4,AL391827.18, AC027319.5, AF168787.1, AC002470.17, U91326.1, AC021188.6,AC074013.5, AC011479.6, AC005098.2, AF228703.1, AC003104.1, AC006013.3,AC010422.7, AC008569.6, AL158830.17, AL118520.26, Z83845.14, AC024075.4,AC007536.9, AC073073.2, AL391803.14, AC005332.1, AL117348.25,AC008946.6, AC004686.1, AC018636.4, AC026172.3, AC010677.4, AC018720.5,AC006211.1, AC008745.6, AL445435.11, AC004383.1, U91321.1, AC004971.3,AC090514.1, AP003352.2, AF001549.1, AC007225.2, AL162615.13, AC010271.6,AC020906.6, AC010748.5, AL139396.17, AC020558.4, AC006121.1,AC011737.10, AL132838.4, AP001727.1, AC020934.7, AC011445.6,AL096701.14, AP000045.1, AF283321.1, AL031597.7, AL024508.1, AC091394.2,AC007690.11, AC019205.4, AP001747.1, AC022211.5, AC011495.6, AP000300.1,AC020913.6, AC002549.1, AC006536.2, AC005821.1, AC004893.1, AC087071.2,AC005529.7, AC009812.17, AC005071.2, AC006965.3, AL157938.22,AP000692.1, AP001728.1, AL445263.6, AC007957.36, AL139021.6, AP000347.1,AC009314.4, AL137792.11, U91322.1, AL022316.2, AC009506.5, AL359092.14,U95090.1, AL049869.6, AC090955.2, AC011467.7, AL139415.10, AC000360.35,AP002007.4, AC007055.3, AC023114.5, AC009086.5, AC007151.2, AL022476.2,AC004965.2, AC011497.6, AP000113.1, AC005052.2, AC004890.2, AC020904.6,AL356915.19, AL050341.18, AC006077.1, AF312032.1, AC008474.7,AC020916.7, AC008623.4, AC008962.8, AC008102.17, AL590762.1, AP000553.1,AC008551.5, AP001718.1, AL162272.10, AC006451.5, AC006023.2; AC004813.2,U91323.1, AP002851.2, AL008721.1, AP000117.1, AL365505.15, AL031721.1,AC004821.3, AL139785.5, AC005701.1, AC006441.13, AP000212.1, AP000134.1,AC034198.6, AC010618.7, AL049569.13, AL356257.14, AC018808.4,AL391136.9, AP000193.1, AC068724.7, AC004824.3, AL109628.5, AC005088.2,AL049757.14, AF288742.1, AC022436.5, AL132780.5, AC010319.7,AC074121.16, AL138849.12, AC004882.2, AP000050.1. HBMUH74 39 8661601-712 15-726 AI633540, BE999936, AL529110, AI911597, AW016785, AA479308,AI381011, AI057451, AI283542, AI224172, AI025510, BF929951, AW589256,AU156824, AU155569, BF063133, R43074, R25758, BF818086, AL529111,BE567017, BE077233, H09061, AA479409, AL136843.1, AK001927.1,AK027756.1, AK001324.1, AC009318.11. HBQAB79 40 810542 1-1317 15-1331BE926412, W27043, BG006701, AW500368, AB020689.1. HBSAK32 41 8563871-578 15-592 AI740936, AI742064, AI832483, BE856354, W89126, AI741855,AA552666, AL525133, AW293469, AI032044, AI769344, AI199155, AL537059,AA769290, AA481420, AA425849, AA968823, R73406, AW290963, AA653956,AA481658, AA244354, BF477489, AI278115, BF664060, N92264, AI014386,N45235, AA723656, AI354229, BE041734, W24441, BE350121, BG109716,R73405, BF690465, AI675727, AL530882, AA570628, AA992527, AW089841,BE858139, C21531, AA029467, AA029534, AI951077, BG004006, AK026029.1,AL442086.1, AL161656.20. HBXCX15 42 637542 1-1205 15-1219 AA595781,AW277007, AI274544, AA548746, AC006329.5, AC009412.6. HCDCY76 43 8379721-1378 15-1392 AI569872, AI384105, AI333327, AW015889, AI376057,AI422820, AI334381, AI358937, BE856323, AW135953, R26141, AA902950,AI092798, W23737, AW970455, AW382273, R26355, AW377602, AW377466,AW852110, BE695760, AI200091, BE695755, AW377603, AW377467, AW852111,BE695754, BE695766, BE695759, AA662446, AB054881.1, AB032417.1. HCDDL4844 839743 1-799 15-813 C14389, AW975618, AW949645, AW964468, AV724520,C14331, AV718692, AV718707, D59502, AW966065, AW966075, C14429,AV718489, D59619, D80210, D80240, D80268, AV699550, AV723927, D80219,AV699746, AV720211, D80212, AW949642, AW966330, AW978634, AV719822,AV718844, AV719324, AV719468, AW966062, AV722801, C15076, D81030,AW966053, AW966389, D51423, D51799, D80253, AW177440, D80166, AW949653,AV720731, AV699447, D59467, D80195, D58283, AW949656, F13647, D80043,D80188, AW965185, AW965197, AW964737, D80391, AW973541, AV719783,AV718800, AV720464, AV718770, AV720203, AW966531, D80227, AW959628,AW959570, AW960553, AW949643, AV719557, D80022, AV699927, AV720791,D80193, D80196, AW949641, AW973447, AW975605, AW966013, AW975621,AW959799, AV719188, AW959582, D59927, AW949631, D80045, AV720878,AW966054, AV718633, AW978661, AW973488, AW960465, D80038, AW973307,AW973334, AV723097, AW966534, AV701357, AV718931, AA305409, D80366,AW949630, D59859, AW973474, AW966029, AV721386, AV718938, AW966041,AW949646, AW949658, AW966050, AW949618, AW962245, AW949655, AV718681,D59889, AV718440, AV720028, AW959597, AW965177, D57483, AW973485,AW966022, D59610, AW965163, D80164, AW966059, AV700889, AW978648,D59787, AV720812, AW975613, AW949629, D59275, AW965184, AW949657,AW973330, AW964756, AW753067, AW965175, AW959202, AW973482, AW958993,AW959136, D51060, D80269, D80024, D50979, AW965158, AW949632, T03269,AW965196, D80378, AW960454, AW960473, AW949654, AW958992, AV699682,D80241, AW959062, AW964477, AW956434, AW964488, AW962082, AV701004,AW964532, AW965176, D50995, C14014, AW966043, C75259, AW956397,AW966030, AW966032, AW960532, AW177501, AW949633, AW177511, AW753053,AW966023, AV718530, AV742048, C14407, AV742001, AV700229, AV738928,AV699669, AW960564, AV701335, D81026, AV742667, D51022, AW975623,AV701043, AV701332, AV719049, AV701017, AV701248, AV701431, AV701149,AW752082, AW959469, AV719628, AW960504, AV720150, Z21582, AV645389,AV645344, AV720533, AV720654, D80134, AW960570, AW378532, AW178893,AV701130, AV701419, AW352117, D58253, AV719913, AV701125, AV701166,AA305578, AW960414, AV744690, AV681510, AV681491, AW973465, AV699866,AW179328, D80949, AV699652, D80248, AV719000, AW960474, AW973490,AW973445, AW966368, AV703738, AV645343, AW973470, D80133, AV745080,AV701422, AV742732, D51250, AV701154, AV701428, AW960514, AV701443,AF271371.1, X67155.2, AF058696.1, D34614.1, AB028859.1, D88547.1,AB002449.1, U79457.1, D50010.1, AB038216.1. HCE1G78 45 761204 1-188215-1896 AW025289, AI935720, BG222525, AA724676, BF844613, BE707252,AW385203, AW580449, AW243018, BE932090, R15390, BF436472, BF351100,AW014134, AA074234, R18788, BF819553, BE162530, H14886, BF087139,AA772066, F35935, R42130, R40003, AI628487, BE169397, R13943, AI540418,BE167881, BF800299, BE142196, AI804744, BE931587, BE166493, AW890237,AL036574, AI675744, R88613, AW607153, BF082899, AW935303, U45975.1,AC005005.1. HCE5F78 46 838101 1-1718 15-1732 AC007318.4, AK025051.1.HCEDR26 47 771144 1-1405 15-1419 AW809560, BF822291, AW805745, T06675,T41328, AW809450, BF884442, BF773357, BF738231, BE163588, BF998055,H00095, BF900030, AA346118, AA644090, BF725844, BF725688, AI919265,AI801505, AW103406, AW855803, BF673854, AA833896, AW958962, AA630854,AI798521, AW855730, AV702109, AA833875, BF725884, AA513851, AW814024,AI537020, AW474825, AW243793, AW275432, AW970064, AC010326.6,AC010645.5, AC010522.3, AL353748.13, AC003006.1, AL136418.4, AL139054.1,AL356805.5, AP000501.1, AP001760.1, AC004840.3, AC007374.6, AL445184.11,AC018738.4, AC008264.10, AC018641.3, AC005102.1, AC007383.4, AC020908.6,AC011497.6, AP000338.2, AC004526.1, AC013356.8, AC011247.10, AL137072.8,AP000216.1, AC006011.2, AC020558.4, AL024498.12, U62293.1, AC004913.2,AC020983.7, AC002044.1, AL355343.18, AC022148.5, AL022316.2,AL354864.16, AL035400.13, AC005529.7, AL109797.18, AC004975.2,AC004895.2, AC002472.6, AP001132.4, AC005881.3, AF258547.1, AC002350.1,AL049776.3, AP002028.1, AC027130.5, AC002558.1, U91321.1, AC008891.7,AC008745.6, AC020913.6, AC004859.2, AF243527.1, AL589723.7, AL031311.1,AC010742.4, L44140.1, AC090950.1, AC026172.3, AL138741.13, AC003048.1,AL137012.6, AC008397.7, AL117352.12, AC005081.3, AL109801.13,AL109798.19, AF258545.2, AL163279.2, AL035587.5, AC010422.7, AC010789.9,AF045555.1, AC011480.3, AC004491.1, AC022217.5, AC011470.5, AP003357.2,AC007283.3, AP001711.1, AC005409.1, AC008812.7, AC008569.6, AF168787.1,AC005082.3, AL158207.15, AL118505.17, AL135927.14, AC007227.3,AC020917.4, Z98949.1, Y14768.1, AC009412.6, AL121992.24, AL117382.28,AC004156.1, AP001694.1, AC007051.3, Z82215.1, AC004796.2, AC073347.3,AC007664.12, AC016776.6, AC020916.7, AP000505.1, AC010328.4, AC004804.1,AC009269.6, AJ400877.1, AF111167.2, AC004167.1, AC007536.9, AC007216.2,AL365364.19, AP001052.1, AL139099.2, AF283320.1, AC009131.6,AL034420.16, AC004755.2, AC000052.16, AC003043.1, AL121891.22,AC002314.1, AC005920.1, AL159977.10, AD001527.1, AL021808.1, AC026464.6,AC005702.1, AL355476.12, AC011455.6, AC009244.24, Z85986.1, Z83844.5,AC004150.8, AL136980.5, AL158823.11, AL158040.13, AL133367.4,AP002392.3, AC000353.27, AC005899.1, AC011489.6, AL035086.12,AC005971.5, AL136087.12, AL445483.13, AL133387.8, AP001752.1,AC009220.10, AC008755.6, AC007993.15, AL138883.12, AL353804.22,AL031767.13, AC009314.4, AC006252.4, AC007666.12, AC019205.4,AL121886.22, AC010320.9, AC009753.5, AC005800.1, AC040160.4, AC004815.2,AL136179.15, AC008536.6, AL096841.6, AC008482.5, AC074142.3,AL109921.21, AC011442.5, AC006333.3, AL158830.17, AC003029.2,AC015982.9, AC012099.4, AL138733.15, AC005412.6, AC027319.5,AC016742.10, AL359092.14, AC012594.7, AL133294.10, AC011005.7,AC007919.18, AL449305.4, AP000744.4, AC005291.1, AC005011.2, AC005098.2,AC009068.10, AL356244.12, AL137230.3, AF235097.1, AL132768.15, Z93015.9,AP001718.1, AC004019.20, AP001720.1, AP001725.1, AC010378.6, AL132640.4,Z82901.1, AL139376.17, AP002852.3, U52111.2, AC002492.1, AC004253.1,AL355353.23, Z82190.1, AL008718.23, AL354932.26, AL031657.5,AL445237.16, AL133448.4, AC007225.2, AL353653.19, AC007390.3,AC008543.7, AC004738.1, AF288742.1, AC006211.1, AC007739.2, AL133545.10,AF111169.2, AL121601.13, AC008474.7, AC004882.2, AC002301.1. HCEEQ25 48531784 1-978 15-992 AW444547, BF514399, AL534267, AI567447, BE747694,BG152517, AW298411, AW865264, AA807579, AA554958, BE889430, AA612578,BF798462, AI078409, AU157259, AI819391, AA643770, AU120121, H77386,AW438907, U78181.1, U78180.1, AC003687.1, AC073838.6, AL157823.9,AC008962.8, AC011005.7, AC002094.1, AC007220.4, AL136984.20, AC020750.3,AL031666.6, AL136110.17, AL161781.12, AC026191.3, AC020744.4,AL031672.13, AL162424.20, AC002425.1, AL022721.1, AL353665.13, Z75887.1,Y10196.1, AL139340.12, AL356257.14, AC021863.5, AC025464.4, AL353812.13,AC090954.1, AC009077.7, AC007956.5, AL117382.28, AC005789.1, AL049555.6,AL035086.12, AC008403.6, AP001754.1, AL035684.25, AC007204.1,AL021395.16, AC020552.4, AC022384.4, AC009137.6, AL157701.2, AC010530.7,AL139113.21, AC010605.4, AL137139.9, AC083866.2, AL035695.17,AC007021.3, AC079175.24, AC010412.7, AL021707.2, AL135927.14,AC007227.3, AC009497.3, AF109907.1, AC008651.7, AL035587.5, AL133259.24.HCEEU18 49 688041 1-1215 15-1229 AL045384, AL042668, AI525108, T85422,AL046089, BE843928, H08562, AA921935, AA815292, AW972431, F23282,BE794230, U91320.1, AC026400.3, AC008469.4, AB018295.1, AL117630.1,AC009032.7, AC003043.1, AC008745.6, AC007405.6, AC018648.5, AL354932.26,AC004867.5, AL117381.32, AC084865.2, AC004967.3, AC013429.12,AL121808.4, AC020754.4, AC005098.2, AC016395.4, AL050335.32, AC005088.2,AC020913.6, AF001548.1, AC004876.2, U91321.1, AF334404.1, AC005279.1,AL355392.7, AC011497.6, AL031658.11, AC008440.8, AC005412.6, AL445222.9,AC005231.2, AC005089.2, AC018711.4, AC019205.4, AC026191.3, AC011490.7,AL161626.20, AL109897.30, Z98051.6, AC011495.6, AL137792.11, AC009087.4,AL133215.16, AC010271.6, AL136305.14, AC004125.1, AC020915.6,AC007052.4, AC004815.2, AC006357.5, AC005944.1, AC004703.1, AC090955.2,AC004019.20, AC004813.2, AC011479.6, AF168787.1, AC012384.16,AC004797.1, AC011443.6, AC005052.2, AC007282.4, AL080243.21,AL031680.20, Z84469.1, AC006116.1, Z84466.1, AC007374.6, AP001717.1,AC007956.5, AL449305.4, AP003352.2, AC006014.2, AL034549.19,AC078962.30, AF030453.1, AC051619.7, AL049761.11, AC006454.3,AC005821.1, AL133551.13, AL157938.22, AL009181.1, AL133353.6,AL031670.6, AC005488.2, AC000025.2, AF205588.1, AC012076.4, AL355094.3,AC011455.6, AC020934.7, AL157372.18, AC087094.2, AC008397.7, AC083863.2,AC005527.3, AC022515.5, AC004966.2, AC009086.5, AC022384.4, AC005056.2,AL049795.20, AC004841.2, AL121825.19, AC002425.1, AL121900.26,AC055120.5, AP000687.2, AC021999.4, U80017.1, AC022392.4, AL132713.11,AC008403.6, AC018644.6, AC036103.8, AC020663.1, AC018719.4, AC027319.5,AL118505.17, AC002039.1. HCEGG08 50 844506 1-2520 15-2534 BF347820,BF340446, BE963976, AV706183, AV702427, AV728270, AV707783, AV706724,BE619195, BF436323, AV725927, AV706746, AV726505, AV658362, AV701611,AV704592, AV723449, AV730781, AV727932, AV732149, AV730288, AV704974,AV751921, AV659189, AV731313, AV752043, AV753374, AV731744, AV725369,AV731708, AA910649, AV702637, AV730547, AV761002, AV760693, AV731977,AV732002, AV731043, AV746276, AV731694, AV726674, AV730711, AV702798,AV662191, AV729983, AV731759, AV752443, AV751555, AV710938, AV731275,AV751573, AV732653, AV730171, AV701237, AV732353, AV730165, AV732155,AI815089, AV757088, AV710534, AV701320, AV730816, AV704916, AV731915,AV656240, AV707088, AV733303, AV756895, AV757887, AV705020, AV756053,AV755874, AV752447, AV758481, AV726067, AV705263, AV711496, AV711240,AV732089, AV710417, AV745906, AV711274, AV732746, AV702869, AV647654,AV728872, AV745415, AA701287, AV758003, AV706104, AV707117, AV727103,AV652156, AV758133, AV710825, AV711567, AV702409, AV763440, AV757553,AV710495, AV723452, AV761270, AV710375, AV728777, AV727189, AV702354,AV707171, AV729129, AV702498, AV714368, AV707686, AV763171, AV702787,AV755473, AV752684, AV709897, AV721645, AV710562, AV710906, AV746382,AV706357, AV707882, AV710935, AV687176, AV755714, H17354, AV725387,AV705234, AV705280, AV725386, AV706035, AV705047, AV757171, AV763669,AV727355, AI338026, AV704611, AV730778, AV709407, AV707685, AV704116,AV752993, AV732200, AV703012, AV730859, AV646736, AV724987, AA725780,AV702581, AV756386, AV757864, AV704924, AV701783, AV728715, AV703417,AV755335, AV701728, AV693117, AV757686, AV757281, AV702671, AV729357,AV702954, AV721318, AV728455, AV730456, AW295635, AV707589, AV709935,AV730866, AV707948, AV726520, AV758766, AV705662, AV697638, AV732255,AV706683, AV723195, AV709356, AV726624, AV745756, AV703591, AV708423,AA580304, AV755783, AA059396, AV726830, AV733811, AV645778, AV726738,AV652808, AV725281, AV706047, AV731653, AV729220, AV704279, AW304383,AV726480, AV706290, AV656004, AV725152, AV699148, AV702537, AI268730,AV702026, AV730018, AV722093, AV728844, AV706814, AV725568, AV705504,AV707798, AI761274, AV730449, AV707690, AV758022, AV710146, AV706889,AV706662, AV757671, AV737377, AV702958, AV652547, AV704981, AV705866,AV703232, AA442825, AV728289, AV731884, AV728249, AV701538, AV706234,AV731793, AV709025, AV703367, AV727576, AV706453, AV705343, AV757673,AV708809, AV706899, AV736429, AV721993, AV701560, AV701586, AV711413,AV701499, AV762873, AV701496, AV705416, AB051530.1, AJ244004.1,AJ244005.1, AJ244003.1, X12660.1, D78345.1, AJ244007.1, U94592.1,D50010.1, D13316.1, AB025273.1, AF144029.1, AJ276256.1, AJ276254.1,X87559.1, Z30183.1, X65235.1, Y14219.1, X82834.1, AJ244006.1, Z16423.1,AF144028.1, AJ276255.1, U45328.1, AB005666.1, R19887, R36218, R36219,R45109, R47916, R48022, R45109, R56735, R56889, R60948, R61616, R69372,R69373, H04883, H10768, H16569, H16611, H17326, H19244, H19243, H26851,H75829, H75830, N78459, W15236, W39643, AA099547, AA099546, AA133785,AA133786, AA135871, AA137176, AA464784, AA491517, H65400, AA902408,AA932084, AA938012, AA436997, AA488171, AA488225, AA897754, AA922133,AA972881, Z39481, Z42770, Z43409, Z43600, T16709, AA947105, F02239,F02924, F06672. HCFLN88 51 610000 1-1420 15-1434 AL526786, BE622815,BE746913, BG167566, BE612603, BE613343, BE543099, AW328570, AI084727,AW511229, BE879597, AA643500, AI090381, BE876617, AW055002, AI744096,AA714840, AI148138, AA598703, AW340721, BE559510, AI125728, AI830384,AU151986, AI885716, BF432640, AI475597, AW339888, AI377299, AI309247,AW005497, AW771450, BE622365, AI139390, AI422379, N95665, AI144110,BF341713, AI919264, AI475648, AI189926, BF809564, AI559248, BE396630,AI817016, AI640708, AA825735, AV662025, BF526593, AI708507, AA935563,AW939178, AW939138, AW939190, AA961207, N66071, N69365, AA603786,AW939128, AI285062, AI826293, AW951255, BF512843, AA620317, AW605529,N80991, AI285338, AW381729, BF956527, AI031873, AW381749, BG056758,AW371517, AW381756, R78288, AI434319, AI282698, AI343784, AW002119,AW169595, N48713, AW371499, AI537993, N26561, R52366, AI916353, R93746,BE828699, AA835499, AW072300, W70306, AA907306, AW748173, N68294,AI468129, BG032430, H89920, AI080137, AA326474, H69097, AA826574,AW303330, AI858652, AI804227, AA322294, AI342977, AA291513, N35677,AI824463, T86711, H49562, Z19236, AI500205, AW966976, AI187820, R78289,AL525884, W76006, BE828722, N81088, F37932, R31642, AA905077, AA922535,AA877249, BF957167, AA780926, BG055657, AW087260, AI202070, AW129497,AA911554, AA045568, R32359, AA204681, AA057054, AA364763, R63145,AI277392, AI886719, BE616036, AW238934, AI082383, BG164867, BG150873,BE548567, BG035187, N91393, BF957863, H69096, R88359, AW328569,BF743483, BF742356, BC001967.1, BC000956.2, AC005089.2, X89985.1,AJ223979.1. HCHAB84 52 834326 1-1345 15-1359 X84712, BF526942, BF036429,BF035689, BF034330, BE878646, BG117306, BE906856, BE871642, AV703538,AW955111, BE729985, BE958344, BE271782, BF698225, BE568321, BG250080,BF826293, BE156569, AW579884, BF977502, AA587630, BE621946, BF512422,BF695706, AV764128, AA448786, AI032411, AA477231, BF695587, AA641139,BE621432, H02682, H02590, H29948, AW972521, AA186733, BF909586, R22544,BE673152, AW405966, AI358557, R22543, BG169787, BF813006, BF742389,AW673871, AA327923, AW392393, AA311766, BF916201, BF742334, R70413,AV763358, AA505606, AA477230, AW794624, AW674083, AA595661, AA579044,AW265468, AA807704, AA642809, AW021674, AA618263, AA405570, BG180320,AA533066, AI702049, AI061313, AI254267, AA084439, AA491767, BG059139,AL042667, AL042670, AA187682, AV763460, BF131490, AA313025, AL121039,AA557945, AW148821, BF901147, AW402784, AA693484, AV758870, AW410844,AW873417, AA601376, AL119909, AI251024, AI444575, BF725761, AW963489,BF857486, AI141202, AA776665, AW069110, AA601290, AW469462, AW270385,AI572680, AW028376, BF817511, AA809116, BF739035, AI064968, AA640310,AA535216, AI679759, AI753113, BF030482, AA600863, AI185160, AW192930,AL138262, BG118544, AW675677, AW023390, AW672927, R67038, AI445699,AI312267, AA659832, AV647070, BF804385, AA610644, AI821901, AV764383,AW105463, BF770715, R83577, AU157209, AI039257, AA602906, AA809546,AW820105, AA502991, AV762112, AI252611, AI567676, AI476049, AA015948,AF126023.1, AF126024.1, BC005943.1, U02057.1, AC002492.1, AL365364.19,AP001760.1, Z68276.1, AC008649.6, AC007842.1, AL157823.9, AL162587.20,AF001711.1, AC021752.5, AC007405.6, AP000133.1, AP000211.1, AC090514.1,AC004922.2, AG013449.8, AL034451.26, AC008891.7, AC020659.5,AL139039.17, AF168787.1, AC010463.6, AC003102.1, AL139353.3, AC006261.1,AC009756.9, AC008946.6, AP000563.1, AC002310.1, AC008068.4, U47924.1,Z69719.1, AL050349.27, AC003048.1, AL359983.7, AC009412.6, AL391839.9,AL031846.2, AL121655.1, Z95324.2, AL389875.1, AC005207.1, AC020716.3,AC009137.6, AP000252.1, AC026172.3, AC006111.3, AP001692.1, AC007333.6,AC005821.1, AB038653.1, AL035684.25, AC005081.3, AC008745.6,AL136300.22, AC005902.7, AC073073.2, AL034418.5, AJ295844.1, AL139317.5,AC020904.6, AF139813.1, AC005519.3, AL445483.13, AP003357.2,AC087239.18, AL049869.6, AC020906.6, AC025280.4, L78810.1, AC008567.4,Z83844.5, AC008821.5, AC009220.10, AC073898.1, AC009311.3, AC004542.1,AC002306.1, AL031311.1, AC016683.7, AL158207.15, AC023105.7,AC006449.19, AL139100.9, AC016594.6, AL356805.5, AC008044.4,AL133517.11, AL133541.21, AC016763.8, AC002554.1, AL020993.1,AC008403.6, AC005355.1, AL121675.36, AL359695.6, AC005261.1, AL163032.3,AL513550.9, AP000511.1, AL589677.6, AC026464.6, AL096712.20, AC024561.4,AC011448.3, AL117348.25, AC010627.5, AC073657.5, AC005288.1, AC010271.6,AP001745.1, AL135783.6, AC090950.1, AF334404.1, AC007055.3, AC008771.4,L44140.1, AL031427.15, AC010319.7, AC007637.9, AL158158.14, AL035086.12,AL451125.7, AC018711.4, AC012085.4, AL135752.6, AC009247.12, Z84466.1,AF053356.1, AC008009.4, AC025165.27, AL133211.9, AL158830.17,AC002551.1, AL109984.14, AC002477.1, AL159168.15, AF205588.1,AC007383.4, AP000146.1, AC010491.3, AC006483.3, AE000658.1, AC004883.2,AC025264.16, AL133230.25, AC007390.3, AF042090.1, AL035455.30,AC005280.3, AC008897.7, AC069255.18, AC011495.6, AC005038.5, AC005914.1,AL136228.8, AP001709.1, AC022211.5, AL139113.21, Z97181.1, AL022323.7,AL137244.28, AE006462.1, Z98048.1, AL133453.3, AF111168.2, AC083884.6,AC010422.7, AP001630.1, AC010458.5, AL353716.18, AL109935.39,AL139316.5, Z94160.1, AC008857.5, AL157372.18, AP002007.4, AC005080.2,AC005412.6, AC008481.7, AC009123.6, AP000356.1, AL137787.11, AC004854.2,AL121886.22, AL133375.25, AC003684.1, AP002392.3, AL121594.6,AC027319.5, AC026185.3, AC005759.1, AC004263.1, AC020552.4, AC032011.14,AC004686.1, AL049636.22, AC007957.36, AJ243213.1, AL139343.9,AC091394.2, AL117381.32, AL163636.6, AC005527.3, AC008521.5, AP002427.3,AL354932.26, AC011891.3, AL138836.15, AC005529.7, AC004975.2,AL442166.1, AB023048.1, AC008555.5, AC011445.6, AC005781.1, AC080011.21,AL121712.27, AC020934.7, AC008372.6, AL031587.3, AL121601.13,AL133355.12, AC026445.4, Z84488.1, AL050347.1, AL161747.5, AP000744.4,AC083876.2, AL359236.4, AL133448.4, AL163284.2, AC008543.7, AC007255.4,AL096701.14, AC010203.13, AL157818.12, AL133312.3, AC005180.2,AC010620.4, AF038458.1, AC004659.1, AC007277.2, AC000353.27. HCMSX51 53788643 1-2239 15-2253 AL520206, AL522291, AL520207, BG115714, BG023953,BF343959, AU133571, BE839880, AW954438, BE264316, BG261277, BE879757,AU131026, BE265959, BE278903, BF725639, AW246741, AA864833, AU148856,BF111640, AA706935, AA431813, N38742, BE857705, BF476344, AU152863,AU125122, AA480041, AW170367, AI094797, AU154528, N48379, BF913004,N26479, AI803158, AL120744, N35219, AW245159, AI089912, AI927351,N20323, AL046695, AA476664, N35530, AI078494, AA015687, AI016568,BE857202, AI587317, AA446620, AW629254, AI433184, AA548282, W03412,N27597, W00855, AA825427, AI128747, AI082265, H38927, BF970202, R48359,AI569253, N29410, N44883, AW014479, AA934555, N41471, AW974179, R15948,AA573084, AA233832, AA017058, W16680, AI312737, R60804, N67483, R15949,Z43237, BE811896, N45053, BE832888, T11764, Z43099, AA431409, R48260,AI933045, AW874096, AW105691, AA336676, AA044969, BF362640, AW893387,AW892550, AW892516, R60299, N35043, T49574, Z41630, AA013473, N35211,AA738419, AA223632, H86402, T49573, AA017209, BF941569, AA635071,AA054652, H86066, AI351292, F02575, N79527, T11765, T35773, AW993110,AW194575, BE893541, AA448030, AI086309, BF737533, AF001690.1,AF029231.1, U96629.1, AB007042.1, AB011091.1, T66574, T66575. HCNCO11 54775086 1-732 15-746 BF926420, BF926408, BF875996, AV705104, AV726755,AW964429, AW950395, AV703435, AV707451, AV707628, AW961373, AV705453,AW964210, AW964423, AV704361, AW952896, AW961510, AV726887, AV729165,AW963643, AV707705, AW963965, AV707556, AV702814, AW963219, AV704916,AV706906, AV703045, AW950229, AV690921, AV704674, AV728297, AV702810,AW960535, AI557262, AW963644, AV708024, AV701594, AV727806, AV727803,AW957298, AV650843, AW957682, AV704283, AV708829, AV701751, AW950078,AW950079, AW949946, AW961329, AW954386, AW954962, AW957974, AW952228,AV725024, AW960663, AW957083, AW950256, AV649266, AV704144, AV703160,AW963857, AW966775, AW958568, AW964298, AW958569, AW966684, AW951998,AV704342, AV703361, AV704848, AV703833, AV703425, AV705771, AV653846,AV728884, AW960406, AW954104, AW945153, AV650865, AV705189, AW958320,AW958316, AV729457, AV728929, AV729285, AV726743, AW949454, AW953619,AW955397, AW949863, AV701787, AW945196, AV708035, AV702901, AW961052,AV701953, AW963108, AV729170, AW958127, AV703284, AV706964, AV728355,AW963612, D50992, AV703367, AV706742, AV703862, AV706047, AV709139,AV652860, AW955394, AV702749, AV708590, AV707020, AW951793, AW951816,AW967188, AV705481, AV706133, AV702435, AV702958, AW955616, AW954194,AW962970, AV726728, AV705420, AV726770, AV695489, AV691061, AW963234,AW955139, AV649942, AW962367, AW964203, AW954242, AW954413, AV727101,AV707189, AW966146, AW951740, AW960600, AW952132, AV703632, AW961431,AW964278, AW958290, AW959722, AV659467, AV706802, AV705998, AV709332,AV705516, AV728913, AV728341, AV709281, AW958045, AW950597, AV707266,AW950411, AW960545, AV705267, AV704712, AV704401, AV702819, AV702458,AV702187, AW965827, AV727386, AW949731, AV707117, AV702298, AV701626,AV727268, AV703465, AW954783, AW953992, AW963581, AW958104, AW950254,AV705154, AW962980, AW957286, AW962378, AW958093, AW963811, AW954221,AV727618, AW963652, AV652536, AW962929, AV704033, AW950520, AW952361,AV701614, AV705518, AV728428, AV729392, AV702035, AV709623, AV702315,AV703266, AV707197, AW945183, AV727756, AV707238, AV706910, AW961377,AW945164, AW950681, AV647033, AV647066, AV647129, AW957628, AW952419,AV707649, AW957779, AV647144, AV702975, D59751, AV650924, AV693604,AW960143, AW963486, AV704876, AV705321, AV652547, AV650877, AW955698,AV707907, AW956167, AW963667, AV703264, AW963401, AV653784, AV727589,AW963641, AW955697, AW955632, AW955629, AV728741, AW961403, AW949521,U94592.1, Z30183.1. HCNSD29 55 862314 1-1714 15-1728 AU130793, AA902780,BG114197, AA675900, BE548792, BE796388, Z78308, BF973800, BF125408,BF382619, BF894864, AA902842, AW083941, BF243278, AW131275, AA155995,AW771771, AA938206, BE251257, AI745367, AA448317, AW511804, AA448455,AI370549, BE139488, AW176079, AA156223, H73833, BF940408, H73162,AW084204, BF062122, AW028149, BF924722, BF433518, AI263130, AA411961,AW071942, BF694503, AA743704, AV764156, BF948901, AW082575, R11580,AA412712, BG153595, BG058948, BF893682, AU130757, BF667868, AF049523.1,BC000273.1, AF049528.1, AK024810.1, U70667.1, AF049524.1, AK023109.1,R34683, R34788, R63327, R63326, R63340, R63341, H15969, H27538, H27547,H27621, H82731, H83344, H83606, H83696, N20620, N32195, N33798, N36103,N36549, N41405, N41578, N44109, W19354, W25310, W38906, W60991, W73124,N89856, AA027859, AA027925, AA034908, AA034975, AA133603, AA133602,AA172294, AA261835, AA262483, AA523928, AA551549, AA563835, AA857095,AA872771, AI095007, AI096629, C05812, C15709, AA247765, AA393650,AA400834, AA487693, AA488710, AA663750, Z21548, AA843596, AA844473,AI041193, AI083985, Z41640, Z46025, Z44537, F03607, D11797, AI262317,AI264408, AI304594. HCQCC96 57 845066 1-2152 15-2166 BF970581, BG117166,AV695085, AV686338, AI341460, AW173384, AV693976, BF032394, BG024316,BE893802, BG254562, AW055235, W39204, BG170478, AW978735, BF572731,AW968956, AI909118, AI909124, AW592429, BG171038, AW118938, AI689438,AI419443, AI801242, AW438695, AI123971, N59864, AA707755, AA974210,AW130020, AA489046, AA768780, AI146982, AW768627, AI093766, AW889585,AW298736, BF111650, AA284319, AA907244, AW874520, AI535676, AW579265,AI955386, AA279581, AA983814, BF185409, BE622718, N59886, AI859864,AI498376, BG171039, BG116650, W01363, AI699807, AA824487, T86598,AA994605, AW044013, T85108, AA489144, AW768600, AA811658, AW271482,BE895361, AI631722, AW021293, R64514, T77523, AA736753, H44608,AI955411, AV689519, N90263, AL119283, H94626, T77559, AL119309, T86597,AI909117, AW376940, N79005, N77027, AW105078, N62828, AI701272,AI334730, T07505, AW848643, AW243861, AI909110, BG007292, BE162291,BE162293, AA532611, AP001816.2, AL022153.1, AC004804.1, AC015982.9,AC006840.17. HCUCF89 58 637986 1-516 15-530 AI524118, BE277210,AL039145, BF698704, BE276480, BE409047, BF698510, BG150796, BF666395,AW089101, BF945647, BE274150, BF699964, AL038072, AU121417, AI630176,AA847952, AW410354, AP001759.1, AC069162.8, AC091529.1, AC018787.5,AL138706.9, AC006449.19, AP000744.4, AK023598.1, AL513550.9, AP001468.1,AC006014.2, AL035691.17, AE000658.1, AC005971.5, AC005049.2, AC002543.1,AL109743.4, AC005488.2, AL121891.22, AL031727.42, AC005182.2,AC006975.2, AK022018.1, AC005725.1, AL035405.10, AL158830.17,AF053356.1, AC008050.6, AC008962.8, AC007912.6, AL137783.12, AL031295.1,AC011515.4, AC004089.25, AL161747.5, AL021937.1, AC068640.29,AC004098.1, AL139081.21, AE006467.1, AC069279.6, AC008055.6, AC013445.8,AC000070.2, AC006050.1, AL022326.1, AL391646.12, AC020658.6,AL121601.13, AC005104.1, AP000946.3. HCUCK44 59 790277 1-1129 15-1143AL532468, BE621866, AL521895, BE621760, BE538472, AL521894, AV734260,AV723629, BE770935, BE790853, AI140351, BE621673, BG168718, BF793790,BE908998, BE545559, BE616433, BE395052, BE621070, BG164550, BF664130,BE937841, AI859347, AV696398, AW977552, BE731169, BE514231, BE312999,BE717043, AV696286, BF726404, BE018100, BE717057, AA121548, AI815642,AA768342, BF326554, BE281457, BF430984, AI864674, AA530873, BF338307,BE717061, BF977210, AA127712, BE676694, AA722381, BE717055, BF971805,BE795728, BE717048, AA987515, AW275917, AA417302, AI354682, AI859814,BF686844, BG035461, AW474962, N92869, AI025466, AA768339, BE396293,BE301588, AI051671, AW753719, BE965688, BE812296, AI920875, AW089493,BE535563, AW190165, R83064, AA130959, BE717112, AA587755, AA045598,N21328, AV712375, AA314322, AA844332, AW578738, AA100477, AI371694,AA043186, AI567303, BE717183, BE891492, BF809525, AI350331, AI039892,AW193146, AA828283, AI952434, BE717068, AW377665, AI289086, AA100476,AI014387, AA917482, BE560356, AA975893, N21020, AA045597, AV758595,AV760858, H94056, AA306867, AA621534, AW406948, BE218977, AI564973,BE741064, AA729835, BF594159, AA417265, AI187288, BE548903, AA661773,BF027132, H80956, W04309, AA649285, AW615725, AI419448, AW088039,N47889, AI952495, R89903, AI816957, BE927438, AI083853, BF029994,AW103201, AA580315, N27984, AI289415, T40562, BF593347, D82429, N80197,AI018462, AA868207, AI873582, AI955989, H81296, BE616655, AW138496,AI833059, AI288157, T91268, R63140, BE044820, BF594190, AA130829,D12288, AA298770, AW952882, AI699667, AI942324, AA310276, W22908,BG165580, AI091426, BE829457, BE829712, BE829791, BE829635, BE829638,AA074395, D12293, BE829628, T91580, AV737050, H81350, BE536089,AA353671, AA053266, AI202414, AI832968, BF382776, AA342277, AW084334,BE833477, W25596, AW886418, BE829841, AA297193, BF797820, AW351513,BF245513, AW377656, T98269, AA342276, D12294, BF086669, BF084242,BE833566, BF084293, AI908913, BF084274, AI868829, BE771088, BF155956,BF084243, BF084295, BF084296, BF086521, BE817957, BF084297, R83013,BF084208, BF084209, BF084211, BE928501, BF086673, BF086541, BF093333,BF089556, BF084298, AI220723, BE928502, BF093356, BF093368, BF093353,BF084241, T85780, BF084260, AA344066, BE870474, AA382073, BF084210,BE253749, BF086528, BF155939, AI310801, BE817887, BF093347, BE928490,AI866230, BE696034, BF084199, BF093349, AI908912, AA807562, BF095869,T91628, AA193223, BF095965, BE747715, AL122042.1, AC007842.1,BC004512.1, AP000892.4, N51146, N74141, AA100050. HCUDD64 60 8350821-388 15-402 BF109963, AI870761, AI149403, BE675981, AI979111, AI590348,AI769440, AA568609, F04371, R68556, N24429, R85927, AW973928, W02539,BG150863, R79201, N69412, R79466, T80848, AI494453, R28549, AW440020,AL390151.1. HCWAE64 61 535893 1-457 15-471 AL043265, BE895962, BF091850,BF924502, BF930204, AW973724, BE906549, BF972009, AA558125, BG163769,AW993087. HDPDI72 62 897277 1-1536 15-1550 AV717810, AC018828.3,AC011464.5, AC022383.3, AC022384.4, AC034193.4, AC002472.6, AC021015.4,AC008119.6, AL356299.16, AC004951.5, AC018808.4, AF003626.1, AP000215.1.HDPGE24 63 801947 1-2611 15-2625 BE876192, AU145980, BE839859, AW953709,AV651029, AW866434, AW866436, AW866430, AV687299, AA604920, AA604512,AI887664, AW813014, BE839866, AA164729, AI566037, AA602341, AA602613,AA214047, BE839860, AI355441, AW855356, AA506540, AU119708, AW855353,AI884345, AV656490, AI049591, AW853687, AW995969, AI963674, BG058784,BF681462, BE811870, AA551394, BE081412, BE672638, AV687875, BE564307,AW935217, BE811892, BE145548, BE563924, AW577107, AV704081, AA631460,AW380640, AA366464, BG012149, BF694965, AW341886, AW866268, AI537997,F29519, AI537504, AI567884, BF874935, AV659506, AW363563, AA631500,AI363970, AA669020, AI270484, H78415, BE709511, AA640505, BE178526,AI989765, AW866337, AW953693, AA484751, AA342969, BF882965, AA484783,AV659374, BE796439, AV695480, AV659391, AW024055, AV659405, AI832956,T81440, AA654981, R70506, BF852810, AA484906, AW997573, AW379425,AI932609, AA631380, AA570339, BE708328, AI597820, BF694852, BE815355,AW934969, AW902128, AV684943, AA366571, BG260565, AA632800, AW007894,AW192258, AI886084, AV764490, H82763, AW131401, T69164, AA605054,AW573583, AA834697, AW858120, AW893702, AW573573, AW074527, AV714931,AW820698, AI679343, AA558871, BF853927, AW438596, BF883928, Z32833,AA503427, AW393438, AA610678, AA522988, AA483882, R95100, AW893701,T59151, AW965008, AA848158, BE067011, T98359, T68422, AI679520,BF935516, AA528276, BE839943, BE929829, AL120269, AV759172, H02561,AV760701, AW802714, BE541237, N21656, AI457389, BE066950, T30343,AI679960, H78215, AV700663, AW978714, AL135377, AA243867, AW151713,AW102955, BF884208, AW157616, BF846275, BG034591, BF106210, BG011353,AA161288, BF883454, AC000353.27, AF001893.1, AC006121.1, AC005484.2,AP001710.1, AL590762.1, AC009961.11, AL035555.10, AL160411.25, Z83822.1,AC022402.4, AL136139.6, AC005291.1, AC007225.2, AC007021.3, AC018828.3,AC010742.4, AL391259.15, AC090943.1, AC090514.1, Z98946.15, AL450263.15,AL034372.33, AC008873.4, AP002812.3, AF224669.1, AC006030.2, AL031311.1,AL122020.5, AL049759.10, AL117692.5, Z94801.1, AC008670.4, AL022318.2,AC008892.5, AC027124.4, AP000555.1, AP001169.1, AC018502.5, AC002378.1,AL390074.17, AC083863.2, AC066597.4, AC002091.1, AC079141.7, Z94056.1,AC005157.1, AL354720.14, AC026391.6, AP001715.1, AC040160.4,AL139109.14, Z97054.1, AC002289.1, AC007450.1, AC007482.7, AE000658.1,AL499604.9, Z84484.1, AP001724.1, AL109865.36, AC066608.5, AC073101.7,AC007850.29, AL137139.9, AL079342.17, AC018642.6, AC007773.1,AC024163.2, AL162231.20, AC007097.4, AL035685.21, AP000352.2,AL021368.1, AF111167.2, AC007363.3, AF088219.1, AC004125.1, AC009137.6,AC018755.3, AL158828.14, AC026398.4, AL356652.19, AC005846.1,AC023510.16, AL355096.4, AC034240.4, AL049713.20, AC011742.3,AL163853.4, AC015982.9, AL138743.5, AC007907.2, AC091492.1, AC021188.6,AC018682.4, AL138878.10, AL390025.1, AC006050.1, AB026898.1, AC011236.8,AC004024.2, AC005214.1, AC002464.1, AL139113.21, AC005046.3, AP000246.1,AP000207.1, AC007563.2, AC005520.2, AL137128.4, AL031670.6, AL442167.1,AL163285.2, AC011816.17, AC024166.3, AC011739.7, AC013734.4, AL021154.1,AC005881.3, AC005697.1, AL022165.1, AL391114.12, AL023513.1, Z98044.13,AC000094.3, AP000129.1, AL139415.10, AC011242.8, Z98304.1, AL589693.3,AL391122.9, AL445435.11, AC003071.1, AF131216.1, AL360272.23,AC087071.2, AC003962.1, AL136123.19, AC020908.6, AP001830.4, AC008450.5,AL445669.9, AJ271736.1, AL034550.31, AL118557.5, AC008891.7, AP000782.3,AP000500.1, AC011464.5, AC011311.11, AL158196.24, AC025262.27,AL049869.6, Z93341.5, AC022468.5, Z92542.2, AL034384.1, AP001728.1,AL031387.4, AC002994.2, AL591807.1, AC022407.6, AL160231.4, AC007065.5,AC005539.1, AL050318.13, U91322.1, AL133415.12, AC010252.3, AC068781.18,AL133500.3, AC008011.11, AJ400877.1, AL390738.4, AC044797.5,AC006445.11, AP000688.1, AL445071.14, AL133545.10, AL035089.21,Z98884.11, AL355535.14, AC007999.12, AC022007.3, AC083871.2, AP000350.1,AL354696.11, U80017.1, AP001671.1, AL121997.7, AC007282.4, AL139330.17,AL049779.6, AL163282.2, U82671.3, AL445928.8, AP001412.2, AC022392.4,AJ400879.1, AL161454.10, AC090957.1, AP001922.4, AC003091.1, AC005971.5,AL121905.23, AL161935.10, AC022267.8, AL158141.14, AC025165.27,AL158198.14, AL160036.12, AL136303.15, AC004707.1, AC012450.9,AF131215.1, AL132657.33, AC006965.3, AL161937.13, AC005969.4,AC018633.2, AC004764.1, AL359846.11, AL118556.4, AF196970.1,AL137787.11, AL360169.17, AC018769.2, AC000052.16, AF190464.1,AL137100.4, AL445248.7, AC008738.6, AC018523.9, AC005670.1, AC010605.4,AC007541.9, AL049795.20, AL096712.20, AC006057.5, AC004019.20,AC006071.1, AC026166.4, AL132640.4, AC022201.4, AC008569.6, AC003049.1,Z84469.1. HDPIU94 64 813352 1-2182 15-2196 AU140297, AL529544, AL529545,AU124978, AI740820, AU116885, AU126162, AW960772, AI565169, BF111956,BG251247, BG177689, BE780814, AI628285, AA482031, BE784432, AA947029,AW954823, AW190175, AA315300, AU143854, AA707674, AI332610, N50136,AU148736, AU127152, AW768480, BF947113, AA223261, AW955931, AI276839,AA189165, AA804584, AA767472, AA223378, AA894857, AA252718, R46372,AA939277, N59367, AA219127, AA774827, AV762911, BE546354, N72682,AA219510, AV761697, AA872005, AW188325, W02461, R21326, AI923716,D29223, R68368, BF771937, BE769443, AA322537, R08745, AA417592, R08746,AW952240, AA299861, AW377015, AA337351, H60482, N76470, BF088734,AA218745, AA336556, BE896274, AI810734, AW118290, BF380800, T30177,D29202, BF910258, AA337527, AA336555, R68574, AI167609, AA376922,AW968355, BF351657, AI832198, AW972092, AW968356, AW972093, AW968729,AI432644, AI623302, AW971740, AI432654, AI432650, AI432653, AW081103,AW858522, AW972091, AW969229, BE672759, AW972090, AI432677, AI431230,AI431307, AI431316, AI431328, AI431353, AI431312, AI432655, AI431310,AW128900, AI431238, AL045327, AI431354, AI432666, AA580821, AI431347,AI431315, BF448552, BE672748, AI432661, AL134524, AI431323, AI431337,AI432675, AI431321, AI492519, BE672745, BE672732, AI431246, BE672719,U46344, AI431235, AI431243, AI432647, AI432651, BE672738, AI431255,AI432674, AI431330, AI432649, BE672767, AI791349, AW601637, AI431248,AI431241, AL042842, AI431254, BE672774, AI431357, AL042729, AI432672,AI432665, BE672742, AL042931, BF589777, AI432662, BE672627, AW577201,AI431345, BE672644, AL042655, AI431351, AL042508, AI431231, AI431346,AL042853, AI432676, AI432673, AI432658, AW128884, AI431257, AW577199,AL042533, AL043166, AL047611, AI431340, AL135012, BE672622, BE672792,AI432657, AL042802, AW128846, AI431247, AI432664, AI432645, BE672718,AL042787, AL042515, AL042832, AI431751, AL043295, AI431314, AI492520,BE672634, BE672743, AI355008, AI492510, AL042898, AI431350, AL043091,AI431318, BE883591, BG167830, BE672749, BE672744, AI682915, AL040207,AW128897, AI866786, AW129223, AL042488, AI432643, AL043278, AK022626.1,BC001240.1, AK001284.1, AF064854.1, AL133074.1, AL133053.1, AL136763.1,AL133049.1, AL133076.1, AL122101.1, AL136755.1, AL136758.1, AL133068.1,AL136825.1, AL133051.1. HDAIY31 65 886159 1-1964 15-1978 AL533296,AU142272, BE560264, BG117407, BE407326, BG116397, BE314927, BE315405,BF205715, AI935180, BE313422, AW965613, BF315382, AI701496, BF727272,BF115518, AI829152, AW474694, H23483, AL040572, AI005000, AA311926,BE297986, AI298282, BE743406, AI675622, AW845300, BF306252, AA037364,AI097581, BF308743, BE296105, AW148771, AI339720, AA455474, BE670969,H23486, T66744, BE818161, R17317, AI268300, AW070382, AI291626,AW409641, AA834030, AI880154, R17812, R13082, AA324613, H23484, T27067,H86644, BF892771, R46701, AA349448, R20964, AA923102, H05150, H23485,T87222, N77062, Z43932, H23020, AW136846, AI742491, AI372678, T16039,T66743, AI372676, R45314, BF681190, H08379, AW864486, AA732753,BE312682, AW864516, H29561, R22677, AA324777, AA774961, R25545, F10589,AI523364, AA379005, T26481, BF904678, Z39993, H06774, H24087, AA670426,R20154, Z42195, R44466, R18635, F07975, Z44889, R59906, AI560142,R53460, R43016, R20237, AI745398, BF904916, H24300, R41995, R53461,H06899, AW801037, T74057, F07778, H08380, AA323177, BF763326, M85501,F12373, BF689358, H08954, R44142, F04562, F01724, F04134, F04226,T15999, AA037520, AA677085, BF335984, R40512, R20492, AL533261,BF858775, R56265, R13207, AA987631, T34814, R42746, BE747609, F09993,AA099781, R63798, R43692, AA902512, AA455473, R55721, F04028, AI984376,AI243094, AA776086, BE504276, BE155765, T10103, Z38178, T16439,BF851177, T10102, BF851176, T16686, BF335999, F01506, BF851173,BE818200, R14040, BF851221, BE814269, BF851178, BE327839, H06858,AW003241, BE394938, BE393786, BF851170, BF884029, H13338, BF858389,AA234656, AW748209, AI393102, R47781, R50313, R50305, AA976743,BF851229, BF335998, AV727501, BG165051, AA323766, AI758272, BG163618,BG113299, AI922707, BG164558, BF037292, BF341801, AV746964, BF792961,BG030364, AA643623, AI702406, BF970449, AW827289, BF921103, BE895585,AW827227, AW827206, AI471361, AW050578, AW196105, BG249582, AV682575,BG108406, AL036736, BE138658, AI345608, BE620202, AI431909, AI345471,AI805769, AI308032, BG027280, AI344785, AL041772, AI452993, AL134999,BG260037, AW983691, AW071417, AI924686, BF753056, BG112718, AI608936,AI963216, AW082594, AI335426, AI348777, BE965355, BF885000, AV735098,AI620284, R40432, AI269580, AI886124, BF814541, AI802833, AW302992,AI812015, BF343099, BF793644, AI799195, AI824576, AW168031, AL118506.27,AK023132.1, AK024508.1, AL137301.1, AK026542.1, AL389982.1, AK024538.1,AL359596.1, AF260566.1, AL137550.1, AL442072.1, BC008417.1, AL359615.1,BC003687.1, AK000432.1, BC004370.1, AL117585.1, AB063070.1, AK000647.1,BC008365.1, AF146568.1, AK026784.1, AF003737.1, AB055366.1, AB063084.1,AL110221.1, AK026462.1, AL110225.1, AL136892.1, AK027164.1, AK025967.1,AK026528.1, BC008280.1, AK027204.1, AB019565.1, AL359618.1, AK026629.1,AK025391.1, AL122050.1, AB050510.1, BC002733.1, AB060916.1, AL359941.1,AF217966.1, AL512754.1, AL117460.1, AK025798.1, AB055303.1, AB060887.1,AL136799.1, AF061943.1, AF078844.1, AK024524.1, AL136928.1, AB051158.1,BC008070.1, AF090943.1, BC005151.1, AF225424.1, AJ012755.1, AL080060.1,BC008382.1, AL137271.1, AB056421.1, AL117583.1, AK000083.1, AB060929.1,AL050277.1, BC003548.1, AK026534.1, AF056191.1, AL136805.1, AL512718.1,AF026816.2, AL137556.1, AL049452.1, BC006164.1, AL137560.1, AK026045.1,AB055374.1, S78214.1, AL133557.1, AK026593.1, AL049382.1, AF271350.1,S61953.1, AF090934.1, AK026526.1, AL390154.1, BC001967.1, AK027116.1,AF177336.1, Z82022.1, AF183393.1, AK026630.1, AL389939.1, BC003684.1,AF090896.1, AK026551.1, AL110280.1, AF091084.1, BC007326.1, AF097996.1,BC002839.1, BC008899.1, AK026959.1, AB060863.1, AB063046.1, AL137459.1,AB048954.1, AK027213.1, BC001045.1, AB052200.1, AF125948.1, AL442082.1,AL136845.1, AL122093.1, AB060214.1, BC007199.1, U42766.1, AK026408.1,X72889.1, BC008780.1, AL137526.1, AL512719.1, AB055361.1, AK026762.1,AB060825.1, AL136768.1, AL583915.1, AK025484.1, AL353956.1, AL133565.1,AL512750.1, BC003683.1, AF113222.1, AK026532.1, AL133104.1, AB052191.1,BC009033.1, AK026504.1, AK027096.1, AB048953.1, AF162270.1, AF218014.1,AL136786.1, U39656.1, AB056427.1, AB063008.1, BC006440.1, X69819.1,BC004951.1, AK025414.1, AK027193.1, AL049464.1, AL137538.1, AK000486.1,AL136843.1, AL359601.1, AB055368.1, AK026927.1, BC007198.1, AF11847.1,AL353940.1, U80742.1, AL117394.1, AB056768.1, BC006412.1, BC009341.1,AL137480.1, AL136749.1, AK000618.1, AK026464.1, AB050534.1, AL133067.1,Y16645.1, AL137557.1, AL110196.1, AK000445.1, AB047615.1, AK026642.1,AK025906.1, AK000137.1, AK026947.1, AK025491.1, BC004958.1, AB063079.1,AK025573.1, AB060839.1, AF207829.1, AK025312.1, AL359623.1, AK025524.1,AK025772.1, AL117440.1, AK000391.1, AF090901.1, AL050393.1, X65873.1,BC008983.1, BC006525.1, AK026647.1, AB048964.1, AL080074.1, AK026353.1,AB047904.1, AL049314.1, AL137648.1, AB056420.1, AJ242859.1, BC001963.1,AB060852.1, AL512689.1, AF219137.1, AL050149.1, AF125949.1, AL050146.1,AL136864.1, AL359620.1, BC008488.1, AL050138.1, AL122123.1, AL162002.1,AL122049.1, AB060826.1, AL049300.1, BC005890.1, AK026086.1, AK026480.1,AB062942.1, AB060908.1, AL512733.1, BC006807.1, AL122098.1, AL117457.1,AK026855.1, AL136787.1, BC005678.1, AL080137.1, BC008387.1, BC003122.1,AL117435.1, AK026744.1, AL136844.1, AK026608.1, AL080127.1, AL136789.1,AL162062.1, AF090900.1, AL133016.1. 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HE2CM39 71 553651 1-552 15-566 AW138760, BG236171, AI928443,AI264363, BF432779, AA581388, BF446513, AW170385, AI366182, AI970247,AA854958, AI354301, AI081061, AI140964, AW243493, AW104079, AI366181,AA732881, AI039682, R46377, AA425694, H11979, AI871576, AI082699,AA428526, AW207325, H72841, AI767870, N35990, AW168999, AI537179,AI678150, AW972093, AI283218, AA405499, Z39960, AI191091, AA626013,AW139286, F03140, AA890408, AI349325, AI871195, AW088879, AI914847,AA192077, AW090285, N95266, AA788656, BE674514, AI634559, AI269823,AA894693, BG109270, AW806761, BG029829, BE965355, AI623941, AI537677,AW169784, AW161156, AI918449, AI538885, AI521005, BF061283, BF853807,AW059828, AI345688, AV743631, BF342261, AI866820, BE138644, AW161579,AI587121, AW302992, BE789764, AI540759, AI348917, AI540674, AI581033,AI349957, AI345005, AW827289, BE048087, BF924855, AL120853, BG164558,BG151388, AW827227, BF812936, BE964614, BG031664, BE047952, BF751347,AW072719, AI648567, AI621341, AI310940, AL041016, AI567582, BE904096,AV750565, BF339322, AW023338, AI698427, AW074869, AA641818, AI859991,BE620444, AV736808, AI874166, AI434741, AV756122, AW268302, BE544111,AI310575, BE878735, BF750879, BG107576, AI307736, AW089275, AI349645,AI919593, AI799674, AI559872, BE910373, AI580674, AW089572, AI568060,AI340533, AI670009, AI921254, AI917963, BE543089, AI890507, BE887488,AI690748, AI340511, AI345608, AW162194, AI473451, AI933992, AW302954,AI800473, AI572717, AL037558, BF753023, BE256001, BE879396, AI288285,AL040241, AI345253, BF680133, AI307494, AI539153, AW151136, AW044029,AI345677, BE138658, AI446373, BE895585, AI340627, AW163834, BE974031,BE963286, AW020095, AV741327, AI494201, BF699668, AI538878, AW263804,BF339594, AI251830, AI813633, AI345745, AI348854, AI345471, AI696611,AI336582, BE886728, BE964683, BE894455, BG114432, AV714085, AV712713,BE965169, N25081, AL037041, AV704350, AI345224, AL119863, BE966699,BG001235, AI868204, BF752999, AA761557, AI267185, AL048323, AW083778,BG249669, BG029086, AA070889, BF904180, AA464646, BG113299, AL048340,AI311892, AW021373, BE621472, AI290153, AL036673, AI335426, AI348777,AW081255, AW772685, AI866770, AI345261, AI702301, BF970449, AW301505,T99953, AI273179, AI805769, BF572734, AL036772, AL036396, AI610357,AA904121, AW058233, BG254745, BF751710, AI436429, BE781369, BF904189,BF726207, BF338002, BF343568, N99092, BE172412, BG166654, AL119791,AA127565, AV755793, AI343059, AA572758, N29277, AW834302, BE890131,BF924856, AW946806, AB063084.1, AL359620.1, AK024538.1, AB050534.1,AL357195.1, AL137665.1, AK026551.1, BC003687.1, AL136844.1, AB048954.1,BC006440.1, AF352728.1, AK026647.1, AL136644.1, AL389939.1, AK026855.1,AB044547.1, AB055368.1, BC009294.1, AL389935.1, AF061943.1, AL512750.1,AK027144.1, AL359622.1, AF028823.2, AL137478.1, AL137547.1, AY034001.1,BC003602.1, AL136768.1, AF090934.1, BC008282.1, AL137463.1, AF026816.2,L19437.2, AK027193.1, AK026746.1, BC000090.1, AF061795.1, AF151685.1,AY026527.1, BC001963.1, BC004530.1, AB049900.1, L30117.1, AK027146.1,AB056809.1, U80742.1, AK026626.1, AB062750.1, BC004244.1, AF205073.1,AL512719.1, BC000051.1, AL136622.1, BC008417.1, AF260566.1, AL050092.1,BC003122.1, AL122110.1, AB063093.1, M64349.1, AK026762.1, AL136893.1,AL049465.1, AK027614.1, BC007499.1, AF111112.1, AK000418.1, BC001236.1,AK026480.1, AL133640.1, AL080154.1, BC001045.1, AF017790.1, BC001056.1,AB049758.1, AF056191.1, BC006133.1, AB019565.1, AB049892.1, AF162270.1,BC009311.1, BC004529.1, AL122050.1, BC002535.1, AK025084.1, AL512733.1,AB056420.1, AK000647.1, AF217982.1, AL583915.1, AL117394.1, M92439.1,AL110218.1, AF271350.1, AL080086.1, BC008196.1, AL512754.1, AL133557.1,S69510.1, AL050116.1, AL122045.1, AL512765.1, AL133113.1, BC008893.1,BC006201.1, S76508.1, AB055361.1, AL137556.1, AK000247.1, AL162008.1,AL136787.1, AK026597.1, AB048975.1, AL137529.1, BC004874.1, AL353940.1,BC006807.1, AF104032.1, X98834.1, BC007053.1, AF051325.1, AK026526.1,AL137574.1, AL137550.1, AB063077.1, AK000310.1, BC002466.1, AL117440.1,AK024546.1, BC004368.1, AJ006417.1, S77771.1, AK026542.1, AK026534.1,AF091084.1, X82434.1, AL122049.1, AL080159.1, AK000432.1, AB050410.1,AK027161.1, BC004362.1, AB060863.1, BC006410.1, AK027182.1, AL389957.1,AB060903.1, AK025015.1, Y14314.1, AL133016.1, AL137558.1, BC001655.1,AL157482.1, AB056768.1, AL080126.1, AL050138.1, AL096751.1, AL136752.1,AL136915.1, BC002733.1, AL389982.1, AL110280.1, U51587.1, AL137476.1,AF230496.1, AK026593.1, AF285167.1, S61953.1, BC008780.1, BC007326.1,AF003737.1, BC004945.1, BC006509.1, AF218031.1, AK025967.1, AK025391.1,AK027121.1, AL512684.1, AK026057.1, AK025410.1, AF218014.1, BC002750.1,AJ299431.1, BC006103.1, AL122106.1, AK000636.1, AF177336.1, AL359583.1,AK026744.1, AL117460.1, AK025632.1, BC007567.1, AL133075.1, BC003548.1,AF090900.1, AF262032.1, AK027142.1, AF125948.1, AF111847.1, BC008078.1,BC002697.1, BC007732.1, AL117435.1, AJ012755.1, AL137479.1, X72889.1,AK027868.1, AK026591.1, AL136799.1, AL080060.1, AL080158.1, AK027102.1,AL512718.1, AK026086.1, AB048964.1, AF217966.1, BC006508.1, AL390154.1,AL512761.1, BC004370.1, AB060873.1, AB060905.1, AB047941.1, BC008280.1,AL133098.1, AK026784.1, AL512746.1, AB047801.1, AF305835.1, AL157431.1,AL133568.1, AL133014.1, AF146568.1, BC006412.1, AK027136.1, AF227198.1,BC007346.1, BC008365.1, AL050277.1, BC006332.1, BC005073.1, AL133093.1,AK000618.1, AL137560.1, BC006832.1, AK026045.1, AF143723.1, BC003650.1.HE2PO93 72 771655 1-1309 15-1323 BG250792, BF340156, BF691370, BE958544,AI913576, BE892390, BE467084, AI769974, BF978990, AI985726, AI978876,AA805536, BG114463, BF976892, AI879646, AI640283, BF212660, BE813503,BF212750, BE245388, AI151263, BE813657, AW994769, AI474103, BF326782,AW078667, N66384, BF382578, BE881936, AI268780, AA137260, BE865738,AW118966, AI690850, BF211945, AA150376, AW020353, AI218961, AI458422,AI758351, BF030723, AA631892, AI350813, AW079202, AI038862, AA150275,BF082705, BF240677, AA912346, T17277, BE003683, BE813513, AW468933,AI003046, BE048238, AA137259, AI208534, BE770261, R77850, AW955572,BF743116, AW183342, AL047998, AA928199, AI282290, AL047999, R77760,BF215622, AL121406, T34660, H60032, BF336987, AA362660, AA330116,Z40410, AW370452, AI473113, AA306043, AA343807, BF239599, AA621093,BF240906, BF887439, BF886985, R40472, N52225, AW168049, AA789087,BE770101, BF885967, AL534441, AA962715, BF212646, N73192, BE871372,BE715872, AC009709.7, AC007911.8. HE6FU11 73 827236 1-1986 15-2000AA992948, AI638341, AW134923, AI038302, H54037, AI581139, AJ007581.1,AK027323.1, AF314058.1, AL021578.4, AB027710.1, AB024964.1. HE6FV29 74588454 1-1512 15-1526 AA984763, AA406303, AA599164, AA600957, BF922107,AL046225, AI623434, BF760969, AI890702, D29050, AL449223.7, AP000114.1,AP000046.1, AP001717.1, AC006039.2, AL078463.11, AL035460.15,AC060232.5, AL161730.9, AF277315.3, AC010198.8, AC010319.7, AC005099.1,AP003114.1, AC020906.6, AL117377.18, AC004841.2, AL161937.13,AC004951.5, AL161781.12, AL157858.5, AL391260.13, AL158828.14,AP000302.1, AC007193.1, AF123462.1, AC027644.9, AC006254.10,AL035662.65, AL139396.17, AC004084.1, AC015937.7, AF008191.1,AL355916.2, AD001502.1, AF283320.1, AC005082.3, AC005399.19, AC003030.1.HE9EA10 75 827796 1-2100 15-2114 AI990816, BG112919, BE503434, AI797355,AW303578, BE502346, AI750156, BE786552, AA514648, AI631128, AU158865,AU148743, AI611129, AU153354, BE540704, AU150538, BF508791, BF223713,N77793, AW103270, AI206873, N62886, AI652672, AW003920, AW515809,AW003207, AI055940, AI039096, AW205084, AI206877, BE175285, AI522151,BE709434, BF436332, AI365206, AI274835, AW798986, AA962334, BF001393,AI220417, AA226874, AA062659, AI696208, AI970440, BF353450. HEBCY54 76600355 1-1175 15-1189 AL530975, AA747512, AI215061, T15637, Z39819,AA350340, AA866209, R00414, AW074717, F08597, AW953260, Z43761,U97145.1. HEBDF77 77 692347 1-1806 15-1820 BE550371, AA991780, BE671948,BE672217, AI907477, BF591700, BE504304, BE220403, BE222339, AI281980,AI015798, BG149662, H29013, R88622, AI656870, H06705, R39800, F07755,Z40840, C15636, C15624, AA133829, H29114, H06754, F06113, T15386,D81469, BE503273, BF062276, BE041662, BE041633, F06114, F02370,AI363908, AW148827, N46729, AA663853, BG149723, BE699475, BG105603,R12748, AL039029, BE699467, BF946316, AB023144.2, AL078460.6. HEBDQ91 78840288 1-1559 15-1573 AW964157, AI564075, AA167586, AW204637, R85100,AA824367, Z45398, AA324333, AA332411, AW341163, T81885, BG055317,AA378561, T05032, BE218722, Z41111, T71210, AV705201, AV703158,AW953763, AC008623.4. HEBFR46 79 847064 1-1290 15-1304 BF339246,AW957665, BG258103, AW075995, BF309372, BE868083, AW576203, BF308177,BE881903, BF689190, AI051657, AA311371, BG059809, W56301, AW058408,AA102223, BE301190, AI091799, R05745, D61582, R01123, AA102222,AA375163, BG029189, AW293550, AI752483, AA376452, AW275432, BF812696,AI439525, AW151541, AW084324, AL121039, AW265468, AI702049, AW162314,AW327673, AA577706, BE273825, BF940118, AI270280, AW148821, AW162332,AA807704, BG059139, AA661583, AW238137, AA601674, BG180320, AV742390,BE244308, AW410844, AI433952, AI828721, AA631915, AL079734, BG152746,AW473160, AW021399, AW020094, BE677164, AA728954, AI860423, AI039257,BF679568, AW243817, AI049999, AW148964, AI538404, AI826857, AI753131,AI690379, BE676856, AI003469, AV758870, BF214695, AW502688, AW631267,AI904840, AA603359, AI251696, AI819419, AI090377, AI254508, BE176819,AI554399, AA112864, AI355246, AW151848, AW962971, AI028148, AI308529,BF868826, BF970107, AA507499, AI751698, AL036896, AC006483.3,BC000787.1, AK024787.1, AC010616.5, AK027150.1, AC004659.1, AL078611.1,AK000385.1, AC005519.3, AC009756.9, AC002543.1, AC005052.2, AL354836.13,AC016995.4, AL023879.1, AC003108.1, AL139824.22, AL121675.36,AL358777.12, AC015651.18, AC011444.5, AC004966.2, AC011526.7,AC010319.7, AL121579.4, AL158040.13, AC007421.12, AC005531.1,AL391259.15, AL096701.14, AC002996.1, AC067945.4, AL109923.29, Z97183.1,AL133458.19, AC010271.6, AF279660.2, AL035086.12, AP000280.2,AL445184.11, AC008440.8, AC008848.7, AL139809.16, AC018663.3,AP000039.1, AP000107.1, AF195658.1, AP000557.2, AC004974.1, AC010789.9,AC004552.1, AC004985.2, AL160256.21, AC018633.2, AL121897.32,AC090944.1, AC020983.7, AP001715.1, AC007374.6, AL117382.28, AF207550.1,AC010422.7, AL137852.15, AC008635.6, AL035659.22, AP000463.2,AB017653.1, AL359236.4, AC005358.1, AL035683.9, AL139785.5, AL159168.15,AC000353.27, AC000379.1, L35532.1, AL357972.18, AC011479.6, AL159990.12,AL138849.12, AC008891.7, AP000555.1, AC010530.7, AC008744.6, AC025212.5,AL451162.14, AF167081.1, AC007240.2, AC003007.1, AL512489.11,AC004673.1, AC004752.1, AL138733.15, AL354948.7, AC011740.7, Z85986.1,AC005484.2, AC013355.7, AC016596.5, AL031711.30, U73636.1, AC006064.9,U91327.1, AL031680.20, AC004089.25, AL132640.4, AL109935.39, AC010326.6,AC007676.19, AL133229.40, AL136228.8, AC018797.4, AL033519.42,AL096791.12, AL391139.19, AC002312.1, Z97054.1, Z83840.7, AC004821.3,AC002060.3, AL139184.8, AC005280.3, AF107885.2, AB032485.1, AP000256.1,AF312032.1, AL035705.22, AC012379.7, AC020904.6, AC008521.5,AL356214.20, AF224669.1, AP000691.1, AC018673.4, U07561.1, AC008392.6,AC004263.1, AP002906.2, AL031058.1, AL355480.22, AC006530.4, AC009362.8,AF258545.2, AL049759.10, AL035249.6, AL008582.11, AJ009616.3,AL050404.3, AL122020.5, AP000098.1, AL133163.2, AC025166.7, AC087311.22,AL513366.11, AL353678.11, Z97632.1, AC005041.2, AL121586.31,AC006449.19, AC010412.7, AL355336.15, AL022316.2, AL353748.13,AC010526.7, AC005911.6, AC016025.12, AC084864.2, AC004066.1, AP001748.1,AC026120.33, AL050307.13, AP000361.1, AL157372.18, AL353710.7,AL049780.4, AC011895.4, AC005695.1, AL161937.13, AL354928.9, AC008738.6,AC008372.6, AP000503.1, AC002404.1, AC008482.5, AL121967.11, AC010378.6,AL449209.2, AC026672.44, AL356805.5, AL031662.26, AL449143.18,AL034369.1, AF134726.1, AL049843.18, AC008623.4, AC072061.8, Z98948.1,AC004662.1, U62317.2, AC012476.8, AC008397.7, Z98752.16, AL161670.4,AC007957.36, AC009399.5, AC008755.6, AF317635.1, AC009812.17,AC002546.1, AC003043.1, AC022211.5, AC007746.3, AL050335.32, AC005015.2,AC022405.5, AC004476.1, AL109804.41, AF001549.1, AC016602.6, AL109799.6,AC008044.4, AC004851.2, AL049795.20, AL162505.20, Z83851.17,AL359541.11, AL031282.1, AC009470.4, AL034422.24, AL133332.12,AC005365.1, AL157789.6, Z98051.6, AC006151.3, AC024561.4, AC009086.5,AC005570.1, AC010679.6, AC009469.4, AC008857.5, AC007845.12, AC005091.1,AL132713.11, L78810.1. HEBGE07 80 798096 1-1853 15-1867 AI016066,AC010170.3, AC006515.7, AC008641.6, AC019086.7, AC016587.7, AL078581.11,AC037433.6, AL121975.9, AC022267.8, AC009225.3, AC091493.1, AC006257.1,AL160411.25, AL033397.7, AL122023.3, AP001671.1, AL121983.13,AL024506.1, AL135785.10, AC079383.17, AC024085.5, AC020552.4,AC087069.2, AC008115.3, AL162571.9, AC078841.4, AC008543.7, AC083876.2,AC005071.2, AC019041.8. HEGAU15 81 834379 1-1111 15-1125 W92008, W92009,AC009404.5. HEQBF89 82 786205 1-845 15-859 AI250552, AI251284, AI251203,AI284543, AW270385, AV759518, AL138455, AA904211, BF337291, AL119625,AI254770, BF725761, AI249853, AA704393, AI251034, AW020198, BE139139,AW963474, AA557911, AV762645, N57681, BE138387, AL037632, AW979191,BE252421, AW020088, AW276678, AL157893.16, AL132656.14, AC007383.4,AC006435.7, AC005952.1, AL133258.16, AP001695.1, AC004987.2, AL096751.1,AL031733.3, AC006443.1, AC006345.4, AL139317.5, D83989.1, AC005015.2,AC023880.5, AF213884.1, AC006994.4, AL449305.4, AL355480.22,AL356244.12, AC006241.1, AC002316.1, AL353802.14, AL035420.15,AL136126.34, AL354776.15, Z98742.5, AC005000.2, AL139081.21, AC010530.7,AL049795.20, AC006064.9, AC023105.7, AF312915.1, Z97352.1, AC004837.1,AL162426.20, D87675.1, AC004686.1, AC007688.15, AL022165.1, AC008736.6,Z83845.14, AL031295.1, AL158052.10, AC026431.3, AP000112.1, AC002477.1,AL031283.26, AC015550.18, AL117336.22, AC018695.6, AL357497.17,AF196779.1, AL121601.13, AC005231.2, AC005874.3, AF134471.1, AC010543.8,AP000089.1, AF283320.1, AC004703.1, AC011479.6, AL022320.23, AP001705.1,AC040160.4, AL163282.2, AL121932.19, AJ009611.6, AC009953.4, AP001726.1,AC044797.5, AL133174.15, AC002464.1, AL050308.9, AC005103.3, AL035587.5,AL034429.1, AL157938.22, AL031577.1, AL137073.13, AF243527.1,AC005940.3, AL359091.10, AL135839.15, AC005519.3, AL354932.26,AL161779.32, AF042090.1, AC004383.1, AC006468.9, AE006467.1, AC006130.1,AC004887.2, AL021393.1, AC008623.4, AC005900.1, AC022405.5, AC024028.10,Z84466.1, AL021155.1, AC072052.6, AL355834.4, AC020956.6, AC005049.2,AC037475.9, AL136450.8, AL445664.14, AL161415.2, AC007193.1,AL353594.13, AP001666.1, AC007686.5, AP000065.1, AC009506.5, AC021188.6,AL121952.18, AC004520.1, AL121903.13, AL121808.4, AC008427.7,AC004883.2, AC011491.5, AL138733.15, AP000501.1, AF047825.1, AC008372.6,AL352978.6, AC002430.1, AC013429.12, AC006254.10, AC008592.4,AL365505.15, AC011742.3, AC005920.1, AC008747.5, AC018711.4, U95742.1,AL161747.5, AC007384.3, AF039907.1, AL139039.17, AL583856.6, AL499604.9,AL353759.8, AC003070.1, AC008622.5, AC084865.2, AC005911.6, AC005480.3,AC008055.6, AC009412.6, AC002059.3, AC004841.2, AL121751.12, AC004139.1,AC009244.24, AC007597.3, Z83846.1, AL139809.16, AP000044.1, AC083874.2,AL050335.32, AC018639.8, AC009298.3, AC006501.5, AL133387.8, AL135928.6,AC021999.4, AP002456.3, AL049869.6, AC005399.19, AC004824.3, AC010422.7,AP000131.1, AP000209.1, Z68870.1. HFEAY59 84 658685 1-1139 15-1153AA339768, AI150703, BE386477, AC005919.1. 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HFTBM38 88 638338 1-1927 15-1941 BF968913, AA570398,BF347068, BF344994, AA326020, AL079872, BE613028, AW838912, BE044516,AA602471, BE672401, BF685077, BF746226, BE326895, AI480220, AI937044,BE061924, BE220469, BE061912, AA325896, AW072853, AI089735, BF330621,AW291237, BE772876, AW964693, AA410930, BE772826, BF747406, AW304942,AW370278, H29431, BF058399, AI862772, AI363103, N94392, AW514350,AA570138, BE772883, AA884986, AA625753, W61300, BF475720, AW070670,BE613183, AA868991, AA325436, BF742302, BE772766, BE772830, BF958918,H29336, BE839173, BE265582, H17864, H29432, BE839167, BE839170,BE772815, R21499, AA323963, AW078921, R42881, BE839096, BE839176,H11141, R49393, H17865, AI668927, BE839166, BE838964, BE839099,AI086318, H43521, BE350499, BE328515, BG056148, AI698485, AI621351,BG060048, H11056, R50356, AA994447, AI479570, AI866814, BF843988,Z41109, AI623712, AI970269, BE839097, T78036, BG109901, H42521,BE839133, H40983, AI419678, AA730385, BE839168, BE839134, W65364,BE083917, R35006, Z45394, AW370252, F07180, H46118, BE925489, AI940302,BF307296, BF871191, AW020419, AA939199, BE781405, AI095222, AW236186,AI653578, AI349957, AI345005, AI345014, AW953817, AW957086, BE878735,AI345261, BG170109, AW967299, AI146301, AA587120, AL120831, BE885353,AW058275, BE138644, BE881363, BF813196, AI421662, BF814072, AI868180,AV682089, AA811656, AI348917, AI690472, AW151974, AI340610, AI287476,AI348870, AV656903, AW302992, Z98519, N75779, AI687568, N25033,AI473471, H12358, AI167594, H89138, AW845239, AW152240, AI334738,AA903145, AL042959, AI340627, AI611728, AI241678, AI348854, BE562685,AI344931, AV757546, BE742905, AI634472, BE974031, AW827207, AA600801,AI632808, AA155840, BG112718, BF872670, BG121551, AI918554, AI784214,AI702301, AW239449, AI630932, BF344395, BE783206, BG167393, AW022682,AW074057, AI584118, AI565932, AI679959, AW129717, BF129016, BF680133,AI267185, BF812936, BF753056, AI468959, AI612885, BF036448, AW081008,BG058217, BF815930, AI879377, AI633225, BE889925, R41605, BE785905,AI804836, BE790023, BF126355, AW083572, AI656270, AW059828, BG105381,AI343091, AI335476, AW189563, BE962830, AW999906, BE613598, BF764538,BG171581, AI309443, AI311892, BE739277, AI307736, BE172864, AW020693,AA582431, AI688848, AV706353, AI349266, BG253683, BG026764, AI349628,AI349246, AI340552, AI584130, AA417278, AI500683, AA749184, AI401697,AI499104, AL045983, AI799189, AI349245, BF969900, AL357752.19,AL132768.15, AC078958.30, AC007719.7, AC073848.4, AL139022.4,AC021325.5, AC009179.17, Z99297.1, AC090498.2, AC079175.24, AC006197.1,AL035407.15, AC018904.6, AL122045.1, AL133069.1, AC006203.1, AL389935.1,BC001963.1, Z94277.1, AC068715.5, U57352.1, AK027115.1, AL121585.22,BC004324.1, BC005151.1, AL136915.1, Y00093.1, BC008070.1, BC007199.1,D89079.1, X59812.1, AF353396.1, BC003122.1, AK000137.1, AK024545.1,AK024622.1, AF117959.1, BC003105.1, AK025117.1, AL135978.4, AL355365.10,BC005165.1, AK025524.1, AK025456.1, AF090896.1, AB047930.1, BC004196.1,AB050410.1, AF218004.1, AK025549.1, AB063100.1, U80742.1, AL080126.1,AL117644.1, BC000001.1, AK026021.1, BC008717.1, AF111847.1, AL136845.1,AF056191.1, BC004119.1, BC000008.1, BC007417.1, AK027104.1, AL359623.1,S77771.1, U77594.1, BC004958.1, AL133629.1, AF192522.1, AF320073.1,AK026164.1, AB056792.1, AB047801.1, AL389957.1, BC002444.1, AK024588.1,BC009395.1, BC001093.1, BC007255.1, AK026744.1, AF113222.1, AL133057.1,AK027188.1, AL137558.1, AL389939.1, BC004883.1, BC000283.1, AL080074.1,BC004368.1, AF025439.1, BC005805.1, AK026590.1, BC001045.1, AK026924.1,AJ010277.1, AL139279.7, AL031274.1, AL442643.2, AL442082.1, AF105427.1,AK026649.1, BC007796.1, BC007609.1, AL133010.1, BC002607.1, BC004156.1,AC007390.3, AL161899.21, AL050310.6, BC004920.1, AF261134.1, BC000348.1,AL162008.1, BC006480.1, BC003052.1, AB063074.1, AF217986.1, BC006196.1,AF060866.1, BC007207.1, AK000257.1, BC000570.1, AL136752.1, AK027136.1,D44497.1, AJ406932.1, AL162062.1, AL135933.11, AJ406937.1, BC008930.1.HFTDH56 89 862021 1-806 15-820 BF105071, AI670093, AI669240, AI151442,AA194946, AW411125, AI808052, AA024998, BF732418, AA700297, H12618,AI688673, AI671406, AA702853, AI078393, BE502303, R66047, AW885572,AI189137, BF512887, AA425375, AI656096, AI287581, AW195085, N93931,R66048, AA195715, AI800331, AI654892, T33449, BF057001, AA195087,H02011, H90799, AA115390, AA195556, AW885729, AA903701, R24216, N98972,AI300252, R24215, AW957374, AA195752, N69833, AA373336, H90748, Z40465,W90007, BF059554, T35437, AA133417, T29924, AA024872, AI473272, W40431,AA425467, BC001087.1, AK027267.1, AC023154.5. HFVHW43 90 570948 1-121915-1233 AI761677, AL047645, BE243506, AA169245, BE246405, AA536127,BE064798, AI364568, AW575409, AW085690, AI298660, AW844145, AA492266,Z23150, AI281401, AA247731, AI078409, AL132795.12, AC009274.9,AL133324.13, AC034245.4, AL158207.15, AC016831.1, AC011491.5, Z82242.1,AC008391.5, AF110184.1, AC004659.1, AL161665.5, AP000689.1, AL158830.17,AL035685.21, AC005000.2, AL353692.14, AL451162.14, AL133551.13,AC005057.2, AL133382.8, AL353614.9, AP000338.2, AC009247.12, AC005327.1,AP000216.1, AC008753.8, AL357519.19, AL157372.18, AL162578.13,AC005722.1, AP000499.1, AC005208.1, AC016697.8, AC005913.2, AL121658.2,AC008745.6, AL137067.7, AC006111.3, AF235097.1, AL050341.18, AC004216.1,AC011455.6, AC079754.4, AC053467.1, AC008755.6, AC005412.6, AC022211.5,AC011461.4, AL121655.1, AL121653.2, AL079342.17, AC009470.4, AC016637.6,AL133347.28, AC004826.3, AB026898.1, AP003357.2, AL391834.8, AC021999.4,AP000744.4, AC022007.3, AC005844.7, AC020754.4, AF111168.2, AC005355.1,AC007773.1, AL139390.15, AC007383.4, AC005104.1, AK022308.1, AC020916.7,AC013429.12, AC012170.6, AL354674.5, AC004150.8, AC004129.1, AC022002.4,AC005839.1, AL136992.22, Z97054.1, AF038458.1, AL158198.14, AL050335.32,AL121920.21, U52111.2, AL136979.16, AC020744.4, AL450346.4, AC004262.1,AL137139.9, AK022406.1, AP001063.1, AL133312.3, AC020550.4, AC002115.1,AP003475.2, AP001760.1, AL499628.1, AL035249.6, AL354928.9, Z99916.1.HGBHP91 91 693011 1-1040 15-1054 AA825851, AA736485, AA805014, AI792627,AI862231, AW086361, AI348722, BE139397, AI254439, AI349662, AI053450,AI053903, AW102980, AC005017.1, AL591770.1, AC005484.2, AC018523.9,AL137190.5, AC016691.10, AL354751.7, AL513366.11, AC009137.6,AC083871.2, AC024166.3, Z77249.1, AL161670.4, AC007934.7, AL137139.9,AB026898.1, AL353613.10, AC018494.6, AL110502.1, AC026770.6, AL031053.1,AC073366.3, AC005014.1, AL138499.4, AL158828.14, AP002982.2, AL133396.2,AC007619.22, AC007327.1, AL022723.4, AC004832.3, AC004491.1, AC005189.1,AC009483.3, AC003950.1, AC009961.11, AL031681.16, AC004813.2. HHEAK45 92765278 1-2000 15-2014 BG170168, BG119757, AU137041, BF307487, AI884713,AW583171, BF684161, BF434422, AI761426, AW961739, BE388217, AI816016,AI361955, AA808964, AU156996, AI869337, AA131094, AW291287, AW043617,AA535378, AW614114, AI249699, AI361947, AI218746, AI827821, AI139529,AI221685, AW961740, AI123285, W72783, AI469925, AL049086, AI076164,AA448078, N79760, AA927285, AI130718, AW103188, AA902207, W74291,AW015957, AW473667, AA447579, AI770126, AA886775, AI001738, AA884899,AI948509, BE467312, AW882943, AI765248, D12320, N72712, AA758092,BE295299, W79163, AI624834, N39042, BF822970, H23141, AA347762, W07208,BE940629, AA889154, AI081857, AI205834, AI377270, AA115546, AI220570,W02262, R42088, AW072212, N93000, R00155, W72784, AA677121, R00154,AI160329, AW450558, AA905549, F04905, H53287, AW262887, AA130970,BE856483, AI632990, W21211, AA115083, AA347763, N48234, AA907343,AI247907, AA665725, H78076, AW366883, AK001963.1, AL035690.10,AC010388.5, AL136839.1, AF086405.1, AC007533.2, AC010209.13,AL133341.12, AC023512.28, AC008379.6, AL033529.25, AL110120.11,AL133271.22, AC006022.1, AL138721.16, AC004694.1, AC005899.1,AL117694.5, AC004129.1, AL359236.4, AL121906.18, AC002465.1,AL133510.13, AL132986.4, AC004263.1, AL512782.6, AL035423.4, AB020867.1,AC008088.8, AC005821.1, AC008012.8, AL138878.10, AC087730.2,AC022509.21, AL391684.6, AL024474.1, AC012499.7, AL356969.12. HHEOW19 94886174 1-1575 15-1589 AL526527, BG113611, BF978449, BG112152, BG119645,AW956161, BG180022, AW592434, BF434127, AI688154, AA890706, BE266768,BE700345, AI192484, AA908255, AA516363, AA446942, AW172490, AA923183,AI499002, AI766675, AI203601, AA894580, AI144379, BF346299, BF969646,AU118533, BE887334, AV760144, BE874811, AA865339, W72592, AW005448,AU143717, AU142574, AA906273, AI021941, AU128074, AW663560, AU131132,AI304388, AA669930, AI304344, AI346611, AU125747, AI311556, AA703026,AI266188, AL516896, AI025716, AA907108, BE390622, AI870412, AI870389,BE785805, AI288868, AA733097, BE789031, BF027056, BF035717, BE870307,BE389154, AL538540, N21316, BE780661, AA075002, AU129647, BG178120,AA774581, BE786810, BG165094, AA075113, AA443366, H70758, BE387196,AI525737, BF346268, AI264657, AA676415, W80864, AA644550, AI023409,AA772235, W67811, AW501988, AI807013, AA299952, AW474224, AI269880,AW629279, BG177563, BF800060, W67866, BF034810, BE547050, BG028159,BE083939, N80176, AI051331, AW592042, BE247222, AI201765, AA860195,AA081004, BE244890, AA019463, N34142, W88877, AI193593, N67021,AI192316, AW795216, N26033, BE084138, BE002622, AI084602, BE774587,BE832659, W76106, AW140058, N42641, BE832664, AA058752, AW994714,AW994775, AI768257, AA018536, AA888922, AW085016, W42800, BE093798,AA706242, AW994696, BE813681, AA384060, AI860208, N46027, AA081147,R96612, AA887957, BE708347, AW993971, AW192384, N41872, BF794279,AU120547, AA370582, BE832568, AW591801, AW236343, AW157602, N40396,AW294314, AW272410, AA723436, W35238, N31251, AA886238, BF817120,BF818982, AA373471, AW131477, H95094, AA808734, AI871211, AL038165,H79809, AI904418, AA534807, AI799628, AA299951, BF361806, AA001163,AA608755, BE798428, BE084059, AA988507, AI761279, AA564284, BE002993,AI949117, BF817107, AV756014, AW384875, AA393462, AW514936, AA454946,AA922856, AW408230, N30627, BE779312, W81429, BF448458, AA876205,H58732, AA831555, BG166267, BF695720, AI743703, N56626, N66943,AA017731, AV684502, AA724567, W24284, BG164949, AW957013, AA724553,H03450, BF056116, AL522121, H03534, W80538, AA193154, N30204, N44250,AA485314, AA485471, AI630146, AA806310, AA400785, AL043900, BE160214,AI338385, N36376, BG014060, AU133112, AW273251, AI218055, BE868284,AA923109, N36810, AA814225, N84302, AA017732, AA313506, AI906913,AI341766, N76206, AI298554, W03500, AW002024, W86743, AA746052,BF365269, W81430, AI351319, AC006001.2, AF098276.1, AC027644.9,AJ250042.1, BC000882.1, AF098275.1, AP002827.3, D13641.1, AC004074.1,AF098274.1, AC008267.6, AC005077.5, AK001702.1, AF126961.1, AF126960.1,AF126962.1, AC005231.2, AF126958.1, AK026600.1, AB060825.1, AC006285.11,AK024538.1, AL122050.1, AC016025.12, BC002733.1, AL137538.1, AB056809.1,AK026927.1, AL136787.1, AK026480.1, AL049466.1, AL110196.1, AB063071.1,AL162006.1, AL122093.1, AL050277.1, AL110221.1, AL110225.1, AK026629.1,AB055361.1, AK026506.1, AK026542.1, BC008387.1, AF091084.1, AK026583.1,AL049430.1, BC001967.1, AB048954.1, BC008070.1, AL133080.1, AL050146.1,AL050393.1, AL389935.1, AF090943.1, AL049452.1, AK025084.1, AK025092.1,AL122100.1, AF090886.1, AL136789.1, AL136586.1, S78214.1, AL136882.1,AL137478.1, AB048953.1, AK026959.1, AL136844.1, AB063046.1, AK026784.1,AL133072.1, U42766.1, BC003687.1, AB019565.1, AK026741.1, AF017790.1,AL133557.1, AL050108.1, BC007021.1, S61953.1, AK027113.1, Y16645.1,AL049283.1, AB047615.1, AK000137.1, AB055366.1, AK025484.1, AL136892.1,AK000486.1, AL133560.1, AB051158.1, AK026744.1, AK024992.1, AK026086.1,AL117583.1, AB060908.1, AK025491.1, AL050116.1, AF125948.1, AF097996.1,AB060916.1, BC001045.1, AL512689.1, BC007199.1, AF217982.1, AL050024.1,AL137459.1, AK000083.1, AK027204.1, AL359615.1, AL442082.1, BC006807.1,AL133565.1, AL049464.1, BC005858.1, AK000618.1, AB055315.1, AB056420.1,AL136893.1, AL133075.1, AL117457.1, AL133016.1, AL157482.1, AL512719.1,AL512718.1, AF090900.1, AL389939.1, AB049892.1, AF218014.1, AK026045.1,AK026647.1, AL049314.1, AL390167.1, AJ242859.1, AL136747.1, AK025015.1,AL096744.1, AK000323.1, AL442072.1, AB060914.1, AL117394.1, AL136749.1,BC008488.1, AL137283.1, AK000445.1, AB060893.1, AL136780.1, AK000212.1,AB062938.1, AB060852.1, BC008417.1, AL137550.1, AL133606.1, S76508.1,AK026592.1, AK027868.1, BC008365.1, AL136799.1, AB060826.1, AF078844.1,AL136928.1, AK024588.1, AB063070.1, AK026855.1, BC008899.1, AK026522.1,AB060863.1, AL117460.1, AK025239.1, AB052200.1, AK027142.1, AB047904.1,AF260566.1, AL136845.1, AF106862.1, AL080124.1, X82434.1, AL137557.1,AL133640.1, AL512754.1, AL133081.1, AL353957.1, AL117585.1, AL359601.1,AB055368.1, AL136768.1, AF090903.1, AL050149.1, AF262032.1, AK000206.1,AF111847.1, AL157431.1, BC004556.1, AL359620.1, BC006195.1, AL122123.1,AB060912.1, AF090934.1, BC001418.2, AL512746.1, AK026526.1, AF125949.1,AL359618.1, AL137521.1, BC007326.1, AK027096.1, Y10936.1, U58996.2,AB052191.1, AL137648.1, BC004195.1, AK027213.1, BC007674.1, AK027200.1,AE219137.1, Z37987.1, AK026452.1, AK025772.1, AL512765.1, AL136864.1,AB062978.1, AK024524.1, BC003683.1, AB048964.1, AL136615.1, AK025339.1,AF225424.1, AL512733.1, AL080137.1, AL133113.1, AF061943.1, AL122110.1,AL137429.1, AK026057.1, AK026353.1, AK027082.1, AK026613.1, AB047801.1,AB055303.1, AB060887.1, AK026534.1, AL080060.1, AL110222.1, AL162083.1,AK027114.1, AK025410.1, Y14314.1, AF146568.1, AF090896.1, AL117435.1,BC008983.1. HHFFL34 95 753230 1-2618 15-2632 BE904333, BE793888,BE878174, BF526368, BF342728, AW958460, BF342223, BE744311, BE728360,BE269184, BE389774, BE728264, AA639278, BE348724, BF685026, BE275174,BF237991, AI913307, BE729585, BG122285, AW021154, AA599241, BE729928,BE700883, BE772076, BF568665, BE700891, BE818932, BF374312, BF330082,BF330070, BE700860, BE700890, BF330075, AW249358, AI128858, BG112722,AA657534, BF330069, BE700887, AW408042, BE180234, AW068020, AA310538,BF568975, AW073205, BF330083, BF372989, BE700929, AW751261, BF363307,BF330096, BF372993, BF330072, BF372977, BG260565, BF330060, AA045741,BF372995, BE700916, AW248940, BF330092, AF074667, BE772071, AV762783,AI753898, BG012246, BF330095, AA352967, BF363296, BE818937, BE772069,AL037632, AV762145, BF372990, BE538259, BF330098, BE707514, BF330088,AV764490, BE909125, BE541237, BG032943, BF363289, BG164166, AL048969,BF363293, AV722075, BF330099, AU119532, BF330063, AV700545, BF372988,AU117926, AW068268, AL044340, BG034591, AW962296, AV714931, AV718718,BF330055, AI457389, AV719402, AV720570, AW963982, BF828714, BG028665,AA984258, BF826830, BF330078, AV759046, BF678427, BE818978, AW407562,BF330073, BE796439, BE396893, BF330057, AL135698, AA577824, AV719941,BF744954, AA284247, AA504646, AW965008, BF679792, BF346320, AA608588,BF330066, BF841650, AV700498, AA680243, AV699393, AW847118, BF673854,AA608612, BE541321, AV700663, AL135377, AW405593, AI732120, AL515875,AV760723, BF372992, AW188427, AI132963, AW962194, AV762693, AA526787,BF363288, AA487475, BF330089, BE004187, BF213459, BE154495, AA328000,AA362575, AA355142, AK027699.1, AK027850.1, AC008764.7, BC007731.1,AK024313.1, Z83840.7, AL137162.25, AC005839.1, AC004655.1, AL022322.1,AL050349.27, AC005781.1, AL023803.3, AL033519.42, AC004000.1,AC011737.10, AC006001.2, AP001726.1, AC007686.5, AC005522.2, AC008622.5,AC010311.8, AC000070.2, AC010203.13, AC013717.8, AC004797.1, AL031577.1,AC002544.1, AC068533.7, AL139317.5, AC019171.4, AC020558.4, AC006241.1,AL034423.21, AC019205.4, AC010378.6, AC011469.6, AC004253.1, AL035587.5,AL109952.15, AL020997.1, AC006511.5, AC007009.2, AC005225.2, AP003357.2,AC009144.5, AP001208.3, AL133545.10, AL021155.1, AC010618.7, AL049872.3,AL159168.15, AP000555.1, AL109752.13, AC068799.14, AC016776.6,AC008440.8, AL132838.4, AC006312.8, AC026172.3, AC002551.1, AC000353.27,AL096841.6, Z69917.1, AC006329.5, AL158040.13, AC079602.15, AL391827.18,Z93015.9, AC073539.3, AC002310.1, AL139809.16, AL136137.15, AC084865.2,AC011485.6, AC008745.6, AC004824.3, AC010458.5, AC004859.2, AC006468.9,AL357314.11, AC008626.5, AL445248.7, AC002115.1, AC006345.4, AJ277546.2,AC024078.4, AL354720.14, AC007546.5, AL109825.23, U91326.1, AC005231.2,AL049636.22, AC007421.12, AC005519.3, AP001748.1, Z93244.1, AC011495.6,AL024498.12, AC005041.2, AC007384.3, AC072052.6, AL109743.4,AL161626.20, AL136313.27, AP000359.1, AC011811.42, AP000689.1,AC011489.6, AC007564.9, Z85987.13, AC009123.6, AC009220.10, AL133353.6,AC004686.1, AC004491.1, AC020612.40, AL365232.24, AP002812.3,AJ300188.1, AC016697.8, AC002430.1, AC010742.4, AC008569.6, AC005899.1,AC005052.2, AL121905.23, AC018738.4, AC040171.3, AC073138.3, AC005666.1,AL080243.21, AL022165.1, AC008427.7, AL034548.25, AC016587.7,AL035659.22, AC026431.3, AC011005.7, AC002073.1, AL049795.20,AC005971.5, AC005562.1, AC021999.4, AL022721.1, AC011487.5, AC002301.1,AL135839.15, AC005089.2, AP000113.1, AP000045.1, AP001670.1, AL589723.7,AC002314.1, AC010677.4, AL034380.26, AC005722.1, AC011470.5, AC006435.7,AC020754.4, AC004873.3, AC005324.1, AL049776.3, AL132780.5, AL445237.16,AC004167.1, AC025165.27, AC007263.4, AL022320.23, AC002319.1, Z98051.6,AC073838.6, AC040160.4, AC018523.9, AL162272.10, AC005056.2, AC002996.1,AL353748.13, AC009131.6, AC005484.2, AC002302.1, AC007536.9,AL050307.13, AC010328.4, AC007707.13, AL160271.19, AF196969.1,AL138784.30, AL121928.13, AL161747.5, AC073073.2, AC012512.7,AC026672.44, AL138724.12, AC004151.1, AC012476.8, AC007374.6,AL121653.2, AL031005.1, AL355392.7, AC011895.4, AC008397.7, Z93017.6,AC011500.7, AL354932.26, AL035071.17, AP001619.1, AL132768.15,AC004019.20, AC007383.4, AC009247.12, AC010422.7, AL023881.24, Z95331.2,AL049694.9, AC008372.6, AP001725.1, AC005102.1, AL359091.10, AC011462.4,AC073657.5, AL354707.17, AL356481.16, AC008687.4, Z95116.1, AC008655.6,AP001711.1, AC018636.4, AL049643.12, AP001718.1, U62293.1, AC021016.4,AL121890.34, AL135924.11, AC004583.1, AL139396.17, AL049569.13,AL163268.2, AL356299.16, AC083884.6, AC003010.1, AC006023.2,AL117382.28, AC010326.6, AL499604.9, AC007688.15, AC004966.2,AC013429.12, AL356652.19, AC011491.5. HHFFS40 96 824059 1-1802 15-1816BE877462, BF792909, BG260156, BG179110, BG112928, BF980559, BE544254,BG170563, BG107623, BF345994, AI763152, BE566242, BF346074, BF672687,AW299766, AI809063, AI658640, AW956747, BG256039, BG255904, AA630311,BE958056, BE873360, BE858485, AW072428, AW590087, AW996985, BE786419,AW963580, BF694200, BE565358, BF669441, AI521984, BF210963, BE564370,BG254405, AA554914, BE877693, BE872103, AI802337, BF242746, AA837003,BE674128, AA704063, AI697970, AI360303, AA676411, AI335019, BF940184,AA758569, AI341577, AI368085, AA976338, AA131990, BF594262, W52093,AI400190, AV655671, AA776953, AI720984, AI969963, BE538461, AI652576,AI924939, AI281274, AA610809, BF999637, BE540644, BF185031, BE564453,BF217183, AA599513, W60435, AI364496, AA622238, BE564859, AA173574,BE564942, AW181884, AA486013, AA452454, AI377701, H57481, AA775104,AA809861, BG110906, AI096469, R22549, AI948687, BG170098, AW467467,BF666042, AA136404, AI914432, AI952665, R72480, W19427, AI651051,R63250, BE768905, AA532466, BE564416, N92774, BE866100, AA487194,AA191014, AA436377, AA419582, N24149, AW072184, H99384, AW962785,AW731695, W52957, AA885982, AA136214, AI000422, AA885090, R73256,AA721779, W59973, AW273180, AI969516, AW996746, AA648637, AW572880,H26458, AA775095, R93450, AA721131, AI866701, BE929433, BF185491,AW129228, AW181995, R80927, AA629087, AV725677, AA486839, AA809868,R64668, R63022, BE247146, BF434557, AW381266, AW129216, D79097,BE925523, AA612598, R93403, AA370728, AA564131, AA330516, AA629088,R62968, AA564772, BE047336, R24143, BF808222, BF807139, AA876640,H58002, AA384569, AW261840, AW361037, AA099083, N40700, AI926874,N27938, AA513948, BF246298, AI499459, BF211955, AW857210, D60986,AA219670, AA247626, AA935365, H58409, AA829160, AA383046, BF960785,AA381919, R14311, BF748705, BE087099, N54068, BE769764, N56083,BE169239, AI583038, AI701882, AW193574, AI886791, AW080675, AA131685,BF954179, T10637, AI619990, AI866695, AI520974, AI446785, AA173533,AI953438, AA746406, BE540062, BF960843, BG014707, BE092961, AA604836,BE720113, AI358254, AI445976, AA190478, BG015664, BF760985, AI634805,AI254727, BF812938, BG110684, AI263312, BG165051, AI554218, BF871413,AI961589, AI915291, BG249582, BE047852, AW026882, BE965621, BF969126,AI637584, AW022699, AI566670, AI590423, AI274759, AW268067, AL514457,BE536058, AI568138, AI431909, BF811804, BF856017, AW104141, AL133078.1,AJ296152.1, AL133113.1, AL389939.1, AF090943.1, BC003682.1, AF262032.1,AK026741.1, AL137527.1, AL162083.1, AL122050.1, AB047904.1, AL512689.1,AL442082.1, AK024538.1, AL133557.1, AL136784.1, AF090900.1, AB060912.1,BC001967.1, AL442072.1, AK025339.1, AL080124.1, AL117585.1, AF146568.1,AL389982.1, AB055361.1, X53587.1, BC004529.1, X69819.1, BC004958.1,AK026542.1, BC008387.1, S61953.1, AF078844.1, S78214.1, BC008893.1,BC004533.1, AF090901.1, AL512718.1, AF090934.1, AK000432.1, AL122045.1,AF207829.1, AL136892.1, AK026045.1, AB055374.1, AB056420.1, AF090903.1,AK026504.1, AL136850.1, AK026526.1, AL050149.1, BC002733.1, AF106862.1,AF104032.1, AL137526.1, U58996.2, AB048954.1, AF125949.1, AL122110.1,AB055315.1, AK025967.1, BC002454.1, BC008417.1, AB055303.1, AB060887.1,AF125948.1, AF061573.2, AB048994.1, AB049900.1, AK026583.1, BC006164.1,AB060873.1, AL133665.1, AL512746.1, AL512719.1, AF057300.1, AF057299.1,AK026480.1, AL049382.1, BC006103.1, AL359596.1, AL080127.1, AL133016.1,AL353956.1, AL050393.1, AL133080.1, AK025391.1, AJ299431.1, AL096744.1,BC008280.1, AL136844.1, AB055352.1, AL136845.1, BC007021.1, AF230496.1,AB049892.1, BC008983.1, AL050116.1, AL359941.1, AB047887.1, AK025312.1,AL137705.1, AL162006.1, AL117460.1, AK025798.1, AB056809.1, AL110221.1,AL117394.1, BC003687.1, AK027213.1, AK026647.1, AL137538.1, AL080234.1,BC003683.1, AL136843.1, BC008899.1, AL136749.1, AL512684.1, AB063070.1,AL110196.1, AB048913.1, AL137459.1, AL137533.1, AL136789.1, AK026927.1,AB049758.1, AL050108.1, AL389935.1, AB049848.1, AL136799.1, BC007389.1,AK026959.1, AL117435.1, AL136928.1, AK026642.1, AB055366.1, AK027164.1,AK026630.1, AL122098.1, AK000391.1, AL133565.1, AK000614.1, BC007326.1,BC002798.1, AK025435.1, AK026506.1, BC006195.1, AK000718.1, BC008488.1,AF091084.1, AL137429.1, X82434.1, AK027096.1, AL137557.1, AL133558.1,AF217966.1, AL049314.1, AK026744.1, AB063046.1, AL137550.1, BC006472.1,AK025632.1, AK000753.1, AL359601.1, AL136768.1, BC006525.1, AL157431.1,AL512765.1, BC004556.1, AL080137.1, BC008365.1, AK024524.1, AL133067.1,AL390154.1, AF073483.1, AB062942.1, AB052191.1, AL049452.1, AL137560.1,AL133640.1, BC004362.1, AL359583.1, AK025084.1, AK025092.1, AK026551.1,AB048975.1, AL137548.1, BC002523.1, AL117457.1, AK026452.1, AL359618.1,AF352728.1, BC004368.1, AL136586.1, AF090896.1, AF162270.1, AK026600.1,AL122093.1, AL050138.1, AL110222.1, AL050015.1, AF097996.1, AL136615.1,BC005151.1, BC004530.1, AB060929.1, AB055368.1, Y14314.1, AK000323.1,AK025484.1, BC006133.1, AK027116.1, X72889.1, AF358829.1, AL133093.1,AB048953.1, AB047930.1, AL512754.1, AL137271.1, AL133075.1, AB048974.1,AL136864.1, AF321617.1, AY026527.1, AL137300.1, AL136787.1, AF061943.1,AK026865.1, AK026855.1, AK000618.1, AF218014.1, U39656.1, AB060863.1,AB060908.1, AJ242859.1, AB047801.1, AK025573.1, AB063077.1, AK000450.1,BC000348.1, AK026592.1, AL050146.1, AY034001.1, AF056191.1, U42766.1,AL133606.1. HHGCS78 97 634605 1-561 15-575 AA523300, AI962903, AA528118,BE858430, AW083553, BE858714; BE893836, AI190409, BE856210, AA769649,AI693556, AI366045, AI609800, AI337942, AW769813, AA613831, AI051792,BE874678, AI799232, AA682810, BE769324, AI810459, BF689177, BF593003,AA705587, BE896233, AI421592, AI421946, AI421527, BE731882, BE855826,AW817923, AI962361, R79580, AA581733, AI342639, AA649978, AI984920,AI624953, AA682704, AW802785, AL119863, BG163618, AL120853, BG029667,AW059828, BF814420, BF792961, AI358701, BF904265, BF338002, AL134259,AL042627, BF970658, AI815855, BG033723, BE393551, BG180996, BG026447,BG114104, AW827206, AV682264, AW411235, BG165051, BF970768, BF970652,BG030364, BF692486, AL038445, AW827103, AV708893, AV709314, AI334445,AV656478, AV684604, AV755884, AL041772, AL039086, BF752245, AV727029,AL043070, AI538764, BG181012, BG058150, BF854113, AV714274, BE876049,AV713662, AV756026, AV647773, AA100772, BG122481, BG105895, BF924882,BE895585, AV729189, AL048656, BF726207, BG113224, BG256880, AL041150,AI312428, BG112718, AV682791, BE966479, AI932794, BE966699, AW129271,AW827227, AW169653, AA508692, BF527014, BF971016, AA853213, AL046463,BG151388, BG105473, BE874133, BF969126, AL036980, AA853539, AL119791,AW301409, AV648263, BG260037, AI073952, BE785868, BE965067, AW238730,AW020095, BF343286, AL045266, AL513907, AI538342, AW827203, AI568114,BE885353, BF752836, AI309401, AL514627, AI784230, AW022682, BF970449,AI554343, BF032768, AI637584, BE885490, AW673679, AI284517, AI932915,BF921103, AI335426, AI348777, AW172723, AI791396, BF312128, AI922561,BE018711, AI344785, BE826053, AV681848, AA420758, BE964614, AI818574,AI671642, AW265004, AL037454, BG027082, AL038605, AW163823, BG029086,BG164558, BE172689, BF061283, AL036274, AV655645, AV647118, BG178689,AI340511, AV682466, AW161579, BE965724, BE779152, BE881005, BG112879,AA427700, AW079818, AI783504, AW827289, BE047852, BF339322, BG029053,BG168185, BE965330, AW238688, BF313411, BG260187, AV755484, BE047952,D50977, N99092, AL042400, AW410969, BG109140, BF672397, BE965192,AW834302, AI866573, AW806761, AL119836, BE837422, BE963838, AL037582,AL037602, BF798503, BF753013, R36271, AW268067, AL079963, AI335208,BG249582, BG179993, BF904193, AI491852, BF968027, AW302992, BE875407,BF038804, AI499986, AI630252, BE965481, AV715359, AW149092, AV743631,BE884296, AV733385, AV758087, BG107410, AI343059, AL079741, AL042628,BF910810, BF909758, AV703169, AW303089, BC005084.1, AF001552.1,AC006221.1, AC073042.7, AC015982.9, AC007458.13, AC083867.4, AP001711.1,AL139099.2, AL355382.6, AB019438.1, AL356800.3, AL389939.1, AL136893.1,AL137527.1, AK027114.1, AL138755.13, AL512761.1, AL162008.1, BC004951.1,AK024538.1, AL080137.1, AL050024.1, AK024588.1, AB060826.1, AK026506.1,AK025254.1, AL136586.1, AL080124.1, AL049430.1, AL359583.1, AF260566.1,AK000718.1, AK025391.1, BC006508.1, AK025375.1, AK026762.1, BC006201.1,AL136749.1, Y16645.1, AB055315.1, BC006440.1, AL050172.1, AK025092.1,U91329.1, AB060912.1, BC008417.1, AK026608.1, AK027113.1, AK000618.1,AL137526.1, AF090943.1, AL133640.1, AL359601.1, AF090900.1, AL133014.1,AL162083.1, AB052191.1, AK026583.1, AL136844.1, AK025491.1, AL136789.1,AL133565.1, BC005168.1, AK027200.1, AL133075.1, AF061943.1, AF162270.1,BC000090.1, AL136754.1, AL389935.1, BC007326.1, AL359596.1, AL117583.1,AL133557.1, AK025632.1, AB060852.1, BC008893.1, AF056191.1, BC008488.1,AL117578.1, AK027142.1, AL157482.1, AK026591.1, AL137476.1, AB048953.1,AK026526.1, AB060863.1, AK025414.1, S78214.1, AL136780.1, AK026600.1,BC006195.1. HHGDT26 98 658692 1-1570 15-1584 AA016083, H38909, H38821,T98933, T98978, AA644090, AA643784, AV700958, AI192440, AL046311,AW961848, AV699675, AV758870, AW408756, AA565911, AW189113, AI275982,AI281881, AW023111, AV761107, AL132986.4, AL020995.14, AC006537.1,U96629.1, Z85986.1, AL359272.9, AL121594.6, AC008450.5, AL139182.24,AF001549.1, AL049829.4, AC005940.3, AC015977.9, AL137000.6, AP000893.5,AC005180.2, AL137100.4, AC006120.1, AL049709.18, AL024498.12,AC008403.6, AC008610.6, AC084864.2, AL035419.12, AC007707.13,AC004990.1, AL096700.14, AL132712.4, AL355392.7, AC009144.5,AL357515.26, AL138720.19, AL121900.26, AC022087.8, AC011484.4,AC002319.1, AC005011.2, AL122021.3, AL138752.5, AC008622.5, AL050341.18,AL157791.4, AC022217.5, AL031311.1, Z98044.13, AC003684.1, AL136985.11,AC005049.2, AL121899.37, AC011469.6, AL356115.9, AL445465.10,AC009812.17, AL121949.13, AC007969.3, AP000501.1, AL049569.13,AC004840.3, AL049779.6, AL022067.1, AL390241.19, AC084865.2, AL133279.7,AL008726.3, AL162417.22, AL136304.10, AL445483.13, AL359792.3,AC007374.6, AC008812.7, AL121928.13, AL137230.3, AL031775.1, AC005088.2,AC004813.2, AC008946.6, Z85996.1, AP001469.1, AC020716.3, AC005756.1,AL096701.14, AC008556.5, AL357752.19, AC011455.6, AC025166.7,AC002316.1, AC005052.2, AC011449.6, AJ277662.1, AL050318.13, AC005077.5,AC010422.7, AC005844.7, AC009123.6, AC008738.6, AC005625.1, AF030453.1,AC005220.1, AL138920.11, AC010605.4, AL117694.5, AC004000.1,AL121582.19, AL031728.12, AC005082.3, AP000471.2, AC005514.1,AC026218.5, L78810.1, AC007055.3, AL162458.10, AC008044.4, AC008551.5,AC011443.6, AC004659.1, AC018644.6, AC020904.6, AP000925.5, AL035398.19,AL136961.19, Z93023.1, AC008040.7, AC073184.5, AB006463.1, AC004491.1,AC018816.5, AC005722.1, AC021016.4, AL132780.5, AC026464.6, AP001717.1,AL023553.5, AC020906.6, AL162424.20, AC004019.20, AC013414.7,AL109935.39, AL359983.7, AC007318.4, U15422.1, AL139415.10, AC008848.7,AF108083.1, AL354928.9, AL109825.23, AC018711.4, AC009364.8, AC009077.7,AC007425.16, AC004531.1, AC010358.5, AP001726.1, AL139022.4, AC010553.6,AL049759.10, AL031283.26, AC004099.1, AC005527.3, AC002351.1,AC011445.6, AF314058.1, AC003663.1, AC004222.1, Z95115.1, AL031680.20,AL031848.11, AC005031.1, AP000167.1, AC021036.5, AC010543.8, AC008134.3,AF260011.2, AC012318.7, AC090883.1, AC004033.3, AC004216.1, U95090.1,AC019066.6, AL358815.12, AC022201.4, AC008372.6, AC006449.19,AC002352.1, AC002390.1, AC010473.5, AP000689.1, U95742.1, AC008440.8,AC005486.2, AL354864.16, AC005225.2, AC004797.1, AP000113.1,ALP000045.1, AC005529.7, AC004675.1, AL030996.1, AL445687.5,AL157712.13, AC002302.1, AC004922.2, AC011895.4, AL138885.21,AC000025.2, AC011742.3, AP000345.1, AC005102.1, AF053356.1, AC018663.3,AP001748.1, AF134726.1, AC004605.1, AC090939.1, AL449223.7, AL109840.24,Z98742.5, AL031685.18, AC007298.17, AC005581.1, AC008733.7, AL589988.6,AF000744.4, AC037475.9, AL355336.15, AC005067.2, AJ246003.1, AC010319.7.HHPFU28 99 824573 1-1824 15-1838 BF035537, AW069711, BF672434, BE883242,AI656112, W31606, W07084, AI272643, AW170657, AA166968, N77917,AW513307, W15523, C75056, AA167046, AA228908, AA228890, AA856550,BE540895, AA856549, AA883954, AI636144, F16318, AW275622, F15813,AA629229, AW979328, BE825903, AA683173, AW954221, AV725561, AV703624,AW962970, AV646649, AB002332.1. HHSBI06 100 639097 1-1035 15-1049BE676485, N59786, AI920783, AA088744, AA779158, BF438300, BE645431,AI915060, AF271897.1, AF285442.1, AF051651.1. HHSBI65 101 801910 1-143015-1444 BE796723, BE541989, BF057278, BF063128, AI990159, AW003665,AW300907, AI738928, AW246641, AW594304, AI521438, AI394059, AA994208,AI130030, AW083104, AA811418, AA974513, AA761013, AA765652, AI583684,AI748894, R67183, AA483531, AA836959, AW236517, H29649, BF115987,AA747573, AA434041, AW845318, T75095, H29565, BE742632, BE386466,AW196291, AI608701, F10461, BE385745, AI474368, BE502390, BF115569,BG236177, BG230771, AI825041, R54830, Aw117865, R38529, AA370939,R43648, AA215393, BE552433, AV749164, BF112242, F13491, BF058839,AI087969, AA215394, AI475583, AW450912, T25126, AA434109, AK026541.1,AF174592.1. HHSDI53 102 862028 1-1263 15-1277 AW994394, AW151201,AW865905, AW865900, AW865898, AW866014, AW865891, AI755214, AW500684,AI754567, AI754105, AW576251, AL042373, AW613805, AW069227, AI923052,AI733856, AW341978, AA847499, BE062476, BE062478, AW576191, AW023111,AA420546, BG059972, AA449997, AW576490, BF911056, BF526964, BF828714,AV763026, AV763058, AW327624, AV732057, AA579179, AA410788, AI358712,AI634187, AU147162, BF691714, AW979087, AU146620, BE062545, AW516255,BF771349, AW328202, AW500029, BG250044, BE676019, AI792529, AW131356,AV703785, AW963663, AV763550, AI249688, AW958962, T74524, AW502873,AV695478, AW474168, AV762430, AI457313, AA828834, AI080307, AI962030,AV759518, AW275432, AW819125, AW026305, BG110162, AV730440, AI421950,AA513851, AI419337, AV730986, AW851405, AU144540, AW964231, AV741914,AV760508, AI038304, BE968744, AL135377, AI636734, AI361090, AV732950,AV754716, AV762009, BG036665, AI345654, AA578621, AW970896, AW021886,AA515048, AI569100, AA557911, AA501461, AL109936.10, AC078815.22,AL079335.29, Z69917.1, AP001760.1, AL136172.16, AC021752.5, AC009470.4,AC009269.6, AL049856.1, AP001169.1, AC008946.6, AC025262.27, AL356805.5,Y18000.1, AL162426.20, AC010271.6, AL121808.4, AL035587.5, AC005694.3,AC011462.4, AL355343.18, AL122001.32, AD000685.1, AC004020.1,AL158198.14, AC036103.8, AB050050.1, AC009570.13, AC011489.6,AC018636.4, AL391280.15, U63721.1, AC025166.7, AC004815.2, AL137128.4,AL109984.14, AC004797.1, AL133349.7, AC034242.5, AC005004.3,AL024498.12, AC010469.7, AC005529.7, AL138824.19, AC004805.1,AL136418.4, AL139054.1, AC017078.8, AC011737.10, AC083871.2, Z97632.1,AL359400.4, AC010654.8, AC005216.1, AC005052.2, AC018690.5, AL031670.6,AC007226.3, AC005932.1, AP000114.1, AP000046.1, AL158207.15, AL121594.6,AC016995.4, AL034372.33, AF064861.1, AC008745.6, AP001717.1,AL136137.15, AF228703.1, AC068799.14, AC074121.16, AP000744.4,AC005086.2, AC007055.3, AL132653.22, AC011445.6, AC011450.4, AC004150.8,AC008760.6, AC012450.9, AF047825.1, AC006451.5, AC005103.3, AC004975.2,AL139316.5, AC005089.2, AL135927.14, AC007227.3, AL121972.17,AC034251.5, AC025593.5, AC011470.5, AP000356.1, AL034548.25, AC021876.5,AC008736.6, AC005725.1, AC010279.4, AC004647.1, AC087071.2, AC002115.1,AC006552.7, AF003626.1, AL137119.26, AC005338.1, AC020916.7, AL133240.3,AL161896.16, AL033378.12, AL359397.3, AF042090.1, AP001725.1,AL161727.15, AL391259.15, AC005200.1, AC009077.7, AC008962.8,AP001752.1, AC004867.5, AB053170.1, AL117381.32, AC010205.5, AC007722.9,AC008440.8, AL354707.17, AC074013.5, AC006449.19, AC007993.15,AC005029.1, AC005180.2, AC010605.4, AP002852.3, AP001727.1, AC004491.1,AL109614.28, AC009068.10, AC006348.3, AL096677.21, AC027319.5,AL445483.13, AC008649.6, AP000555.1, AF001549.1, AC011510.7, AC002316.1,AC006203.1, AC008403.6, AC004755.2, AL358815.12, AC006000.2, AC027644.9,AC005098.2, AL159159.21, U78027.1, AC073838.6, AC002126.1, AC004771.1,AL121653.2, AC016587.7, AC005880.3, U91323.1, AL121601.13, AC005924.2,AP001053.1, AL022312.7, AC007388.3, AC004967.3, AL096840.25,AC004166.12, AL354932.26, AP001718.1, AC011465.4, AL353679.18,AC010463.6, AL121992.24, AC020754.4, AL049610.9, AC006441.13,AC006483.3, AC005620.1, AL136039.4, AL031295.1, AC008280.4, AC008397.7,AL161907.17, AL035422.12, AC004821.3, AC009220.10, AC004895.2,AC009509.7, AL137818.3, AC004125.1, AF031078.1, AC002352.1, AL356020.3,AC008474.7, AC002546.1, AL159997.14, AC007565.1, AL117382.28,AP001631.1, AC000082.4, AC007011.1, AC004813.2, AC008392.6, AF030876.1,AL137005.6, AC013719.8, AC005779.1, AC002401.1, AC002090.1, U91321.1,AC025280.4, AL445222.9, AC008569.6, AP003475.2, AL031228.1, U95090.1,AC016742.10, AL359711.18, AC068533.7, AL138836.15, AC004922.2,AC004840.3, AL021579.1, AP000694.1, AC005522.2, AF111167.2, AL022320.23,AL136220.14, AL031311.1, AL138741.13, AL354889.14, AC007664.12,AL356747.18, AC000003.1, AC007324.55, AL033397.7, AL359552.16, Z83844.5,AC021868.17, AL136170.12, AC016894.7, AL136228.8, AC007283.3, Z83308.1,AC005236.4, AP002342.3. HISAT67 103 843549 1-2140 15-2154 AL519801,AL520029, AL521674, AL515614, AL519807, AL519808, AL526569, AL519802,AL520030, AL535434, AL521675, AL515615, BE798433, BE797403, AL528668,AU130192, BE745046, AL535433, AW177988, AW177985, BF526765, BE741361,BE546284, BE882894, BE745446, AI924136, AL524747, BE902340, BF796576,BF314225, BE622034, BF237909, BE257929, BF306879, BE617643, BE867904,AW374088, BE617000, BF688830, BF345850, BF688351, AW960985, AA252420,BF817742, BE622673, BE535410, AI183729, AW438568, AA769320, BF816143,BF541658, AI274790, AA058936, BF530326, BF345429, BE568171, BF315183,AA827859, AI150987, BG104230, AW192463, BE383533, AW769453, BF195400,BG253720, AA699494, AI298600, BE395450, AA411591, AA976201, BF246062,AA565575, AI811947, BE838606, AU155423, AA425979, AA548944, AI096361,AA151497, AW087834, AI361378, AI085749, AW027881, AA426271, AA613326,AA687138, N81134, AA411464, BG222316, N35214, AI299858, AA394068,AA088263, AI150914, AA889019, AA252504, H83961, AL045552, AI689551,BE819030, AI089337, BE565997, AI803858, AA151552, AU134447, BF347858,AW247185, R40419, AA351639, H58370, AI362586, AI631415, AU157064,AW406063, R69998, BF132861, AA292350, H06495, R13035, AI858744,AW392518, AW517903, AI539838, BG169732, AA564447, AI280222, AU137181,H58371, AA355297, H11618, R74275, AW606537, BF825915, AA478985,BF914457, BF247267, N90293, AA324676, BF913845, W04666, BF695749,R39793, AI932851, AA629936, AA300144, AW731758, AI886965, AA477921,AA580861, AA632377, AW957318, C02190, AW089325, AW402477, R37205,R31157, AI633079, R12741, T34011, BF527821, BE819060, BF761740,AW139230, AI369955, AI579955, BF244267, R74188, R27176, Z17827,BF874647, AA877093, BE819032, AA582577, BF435602, F32545, N75291,N99252, T25048, AA467840, AW392536, AA467896, AW968190, AI085046,AA151496, H83960, AA468217, AW607357, AW631248, AW051088, AI360195,BF792469, AI610402, AI249946, BF753056, BE069307, AA514684, BE909285,AL042544, AI921167, AI002285, AI815855, AW163834, AA888196, BG029053,BE047833, AI698391, BF927081, AI923989, AV756026, AW118508, AI887775,BE965481, BG121959, BF813196, AV756182, BG029667, AI582932, AW059828,AL037454, BF814761, AV681848, BF726183, AA830821, T99953, BE877142,AW009306, AW161098, AA420722, AI452857, BE245461, AI345745, BF969807,BF918076, BF921291, AV735098, BF529088, BE536263, AV708119, BF529870,AV727839, BE964614, AI500061, AI696626, AI633125, BF885000, AI915291,AF203687.1, BC002765.1, AF226684.1, AK023064.1, BC008658.1, AF227166.1,AK023405.1, AK001976.1, AF125949.1, AL133560.1, AL359618.1, AL110225.1,AF090901.1, BC008488.1, AB049892.1, AB047887.1, X86693.1, BC003548.1,AL133080.1, AL110221.1, AF091084.1, BC008387.1, AB051158.1, AK000323.1,BC004310.1, AF090903.1, BC006201.1, AL133606.1, BC004297.1, BC002975.1,AY033290.1, AL512689.1, AK025484.1, AK026462.1, AK026528.1, AB060863.1,AK026480.1, X72889.1, AK026542.1, AL512750.1, AB063070.1, AB056809.1,AK026504.1, AF097996.1, AL050024.1, AL122050.1, AK026583.1, AL049314.1,AK000083.1, AL137533.1, AL117394.1, AK024538.1, AL133640.1, AK027142.1,BC004556.1, AF106862.1, AL049464.1, AL137560.1, AK026744.1, AL137538.1,AB048975.1, AK000486.1, AL512733.1, Y16645.1, AK025967.1, AK027160.1,AL117435.1, AL137550.1, BC006807.1, BC004908.1, AL122110.1, AB060826.1,U39656.1, AL133081.1, AB055366.1, BC004958.1, AK026927.1, AL050146.1,AL137660.1, AF078844.1, AK027113.1, AK027096.1, AK025092.1, AF217982.1,AL136792.1, AK026434.1, AL137480.1, S78214.1, AK000445.1, BC001967.1,AB060832.1, BC001045.1, AL117585.1, AK026534.1, AK000614.1, AL137283.1,BC008899.1, AF069506.1, AK026959.1, AB060908.1, BC003682.1, S77771.1,AK000291.1, BC003684.1, AL096744.1, AL050393.1, U42766.1, AL133031.1,AL136805.1, AC068715.5, AK026647.1, AB055361.1, AK026353.1, AL050277.1,AL049430.1, AK026164.1, AB062938.1, AK027081.1, AF090886.1, AK025772.1,AL122093.1, AB052191.1, AL122121.1, AC025226.4, AL136799.1, AB019565.1,AL137429.1, X82434.1, AF090934.1, AF090943.1, AL137557.1, AB048953.1,AF277181.1, AL512684.1, BC008284.1, AL136786.1, AB047615.1, AK026642.1,AK025339.1, AL137271.1, BC005168.1, BC008844.1, AK025209.1, AB056420.1,AK026784.1, AK027200.1, BC006525.1, AL117457.1, BC009355.1, AF260566.1,AL157431.1, AL512765.1, AF146568.1, AL136845.1, AL133113.1, AL137527.1,AL133565.1, AL136784.1, AF232009.1, S61953.1, AL035458.35, BC007326.1,BC001774.1, AL136640.1, BC007548.1, AK025414.1, AK027204.1, AK025491.1,AL359601.1, AL133016.1, AK025708.1, BC004119.1, BC009113.1, AL442072.1,AL353940.1, AL353956.1, BC008004.1, AB055315.1, AL137555.1, AJ012755.1,X98834.1, AK026608.1, AL137300.1, AK000652.1, BC002978.1, AL162003.1,BC006164.1, AB048954.1, AB060916.1, AK025632.1, AL133077.1, AF111847.1,AJ010277.1, AL049466.1, AL137548.1, AK026526.1, AC019176.4, BC009010.1,AF225424.1, AK024588.1, AL512754.1, AB050534.1, AL353957.1, BC004951.1,AF177336.1, AL359596.1, AL136844.1, AB063046.1, AB048974.1, AJ242859.1,AB060857.1, AB060852.1, Y14314.1, AL050116.1, AL050108.1, AL136825.1,AL137521.1, AL122123.1, AF230496.1, AK026506.1, AK000212.1, AK025383.1,AC069298.8, AL136790.1, AL162002.1, AF026816.2, AK027114.1, AL389939.1,BC003687.1, BC002647.1, AK026741.1, AF218034.1, AL512746.1, AB060825.1,AL136843.1, BC008719.1, AB055303.1, AB060887.1, AF090900.1, AK026452.1,AB049758.1, AL442082.1, AL133047.1, AK026551.1, AF106934.1, BC004191.1,AL389982.1, AC005876.3. HJBCU75 104 638329 1-995 15-1009 AA789332,AI925535, AW469963, AI925543, AA312696, BF732842, BE670545, AI685010,AW962841, AI690167, AA570056, AA470465, AW969303, AW770920, AI634463,T95424, T95333, AW080646, AW003925, BE617765, AI468303, AA311608,AW268987, BE669814, AA356443, BF690832, AW753521, AA682679, BE962309.HJMAA03 105 824062 1-651 15-665 AW304711, BE677684, AW959142, AI290480,BF090788, AW571568, AI092037, N55492, BF090740, W05027, BE714108,N76979, AA361785, N70383, C02489, BF987194, BF087284, BF087325,AA732983, AI348883, AV682863, AW305097, AV691827, AL038473, AW265139,AL442128.7, L44140.1, AC004867.5, AC004166.12, AC009996.7, AL135905.6,AP000087.1, AL158158.14, AC018809.4, AF190464.1, AL391839.9,AL035684.25, AC007172.6, AP001694.1, AC009753.5, AC007383.4, AC026431.3,AP001623.1, AC002558.1, AC068533.7, AL133243.1, AL161670.4, U52112.1,AL135839.15, AC084864.2, AC005180.2, AL359265.8, AC020716.3, AF287262.1,AC024082.6, AC002551.1, AC010267.6, AL160471.5, AC004883.2, AC007225.2,AL359091.10, AC020663.1, AP001710.1, AL121972.17, AP001746.1,AC006111.3, AC079684.16, AL035086.12, AL031670.6, AL135744.4,AL391827.18, AP002515.3, AC005098.2, AC018639.8, AC087071.2, AC002565.1,AL354932.26, AL160269.14, AC087244.17, AC004491.1, AC018751.30,AC083884.6, AC007308.13, AC083868.2, AL031587.3, AL035458.35,AC004878.2, AC004832.3, AC002316.1, AC003950.1, AC006486.1. HJMAV41 106862029 1-1003 15-1017 AL519996, N99345, AL528860, BF967736, AL528859,AL532599, AL538083, AL538011, BF527376, AL535063, BE967933, H21178,AA424063, BF529494, BF507682, AW297516, BF342788, AI422769, AI185878,AI124739, AI865987, H21121, AI816490, H18325, H21179, AI703250,AW592816, AI784327, T03789, AI369670, AA378946, H41697, H21831, H23884,BG056097, R59872, R87479, R90915, H21832, AI174201, H41664, H21166,AL519997, H41609, AL533018, AL533068, AL533347, H46526, H43588, R50960,H43587, AW162319, H18324, T23814, AA378559, AA378947, AW954445, D54991,BE504938, AA424113, R40163, Z38418, AL534514, AL537105, AL538012,AW156888, H46527, BF945915, AL534591, R38431, BF904209, R41229,BF983417, AL538084, BE967687, AF186264.1, AC003112.1. HJMAY90 107 7936781-2872 15-2886 HJPBE39 108 801960 1-1284 15-1298 AL519852, AL527399,AL515498, AL527358, AL529347, BF792443, AL515497, BE730880, BE277609,BF000393, AI962602, AL525722, BE730832, BE384867, BF686529, BE795039,AW263053, BE888955, BF304919, BF315024, BG031037, BE389217, BE049408,BE390060, BF984396, BE388113, BE348265, BF973110, BE266542, AI671396,BE867694, AI393247, BE311766, BE207532, BE544851, BE397321, BF125789,AI688503, BE616765, AW084179, BF036778, AI215805, BE276965, BE274028,BE279716, BE220591, BE886536, AV721055, AA666401, BE730577, BE266808,BE787679, AI333898, BE391366, W16684, AW952000, AL529348, BE385658,AW448966, BF307353, BE302707, AL519851, BE265722, AA186873, AW769101,BE615964, AW246258, AW235139, BG025833, AI983116, BG119203, AI767753,BE384303, BE273943, AA312411, AI948835, AI312519, AA733032, AA838388,AW673726, AW672758, N79531, AI968691, AA055433, BE263201, AI370568,AW615793, AI745361, AW675422, BE328771, AW135640, AI691056, D11879,AI352285, AW272223, D11592, AW241457, AI568807, D11608, AA583830,BE263003, BF678146, W27625, AA877583, AA099966, BF349610, AW673090,T30363, AA759230, AW672670, BE925766, AA641441, BE937913, AA188528,BF240905, AI942377, BG025864, AA055004, AW999828, AA362916, BF790356,BF332109, BC004169.1, AP001486.4. HJPCH08 109 840365 1-865 15-879AI655312, AW975835, AI653243, BF059498, AA731744, AW590208, AU154664,AI671173, AI669341, BF970492, AA704870, AI654412, AI889336, BE966747,AI739117, AI168283, AA781842, AI203090, AW383906, AW103151, AW589549,AW074368, AA600977, AI014854, AA179845, BE775064, BE090424, AA630744,AV714379, AW857113, AW075406, BF982048, AA736497, AA789069, AW770138,BE696241, BE622755, AW074752, BE928343, BF762364, AI904387, BE539952,AA471345, AF153329.1, AF070672.1, AK024804.1, AK025790.1, AC004826.3.HKGBF25 110 738797 1-1993 15-2007 AV763026, AV763058, AA410788,AU147162, AI133514, AA449997, AW805539, AA811741, AA713765, AW002831,AA488689, BF769368, AA721645, AI380617, BF528591, AU153296, AI342183,BE140949, AI056177, AU157093, BE178231, AW571963, H73550, AU150634,BE178064, AI590458, AU153624, AI278847, AU151428, BG250286, AA587516,AW075132, AA456924, AA228778, AV762633, AA922351, BF834843, W60612,AW805547, BE142845, AA176604, AI538491, AI434037, AA745383, AL042310,AU154011, AI690497, AA586866, AI590499, AV741914, T06598, AA808173,AA845659, AI054030, AV760918, AW978041, AL134418, AI355080, AW067788,AW504299, AW068008, AW068007, AV738383, M37468.1, AL138752.5,AC007298.17, AC040160.4, AC008812.7, AC008521.5, AP001712.1, AC008766.4,AL035587.5, AC009068.10, AC087071.2, AC011462.4, AC009247.12,AL160237.4, AL035634.7, AC007000.2, AC011445.6, AC008397.7, AC000118.1,AL161911.17, AL133260.12, AC006312.8, AL121899.37, AC005522.2,AC007842.1, AC007993.15, AC007956.5, AC011295.3, AC005015.2, AC011449.6,Z97196.1, AL121926.24, AC004253.1, AC005884.1, AF196972.1, AC022007.3,AC007676.19, AC003982.1, AC004686.1, AC011742.3, AL122035.6, AC018809.4,AL138743.5, AL359986.15, AC004217.1, AL353807.18, AC078818.19,AL161731.20, AJ400877.1, AC006483.3, AC022392.4, L78833.1, AC007052.4,AL096700.14, AL049569.13, AL031668.23, AC026391.6, AC091637.1,AL050317.16, AC007597.3, AC003043.1, AC006001.2, AC025588.1,AL161656.20, AC007679.4, AC005988.1, AC018682.4, AC005940.3,AC005399.19, Z98751.1, AC005004.3, AC005081.3, Z85986.1, AF053356.1,AL160166.10, AL583856.6, AC026770.6, AL031230.1, AD001527.1, AC004983.2,AL031584.1, AL138832.10, AL137797.9, AC024561.4, AL355886.4, AC018868.4,AL121658.2, AC074013.5, M63796.1, AL161893.24, AC004841.2, AC011736.4,AC006994.4, AL121972.17, AP000424.3, AL391280.15, AL034380.26,AL022316.2, AC006337.4, AL121656.2, Z83822.1, AL050349.27, AC010311.8,AC010616.5, Z97054.1, AC011484.4, Z99716.4, AL354696.11, AF243527.1,AC007225.2, AL050341.18, AC011450.4, AC006013.3, AP001717.1, AC005412.6,AC010077.1, AC068799.14, AC011247.10, AC018695.6, AC006006.2,AC002350.1, AL445222.9, AL049709.18, AL132777.4, AC007707.13,AP001725.1, AC004263.1, AL096701.14, AC067941.7, AL121936.17,AC011500.7, AC005624.1, AC005103.3, AC004408.1, AC010913.9, AL031597.7,AC009144.5, AL035407.15, AL031005.1, AL117381.32, AC005332.1,AC008481.7, AL035419.12, AC003950.1, AF168787.1, AL158040.13,AL354815.10, AP001718.1, Z85996.1, AF207550.1, AP000193.1, AP000131.1,AP000209.1, AC020552.4, AL133243.1, AC003958.1, AC009480.4, AL355137.23,AC005355.1, AC072052.6, AC004805.1, U91323.1, AC005480.3, AC011497.6,AL353706.6, AP001767.4, AC002316.1, AL357515.26, AL117337.25,AL162740.13, AC004890.2, AF047825.1, AC009570.13, AL031447.4,AL032822.1, AC007536.9, AC006597.2, AC007365.3, AL023876.2, AL008732.1,AL354932.26, AC005102.1, AC005080.2, AC002492.1, AF030453.1, AC008440.8,AL513008.14, AL162293.22, AC010724.6, AL031003.1, AL162430.15,AC005088.2, AL031657.5, AP000248.1, AP000117.1, AL096791.12, AC003665.1,AC010279.4, AC007382.3, U47924.1, AC024584.5, AP001714.1, AC008556.5,AL035249.6, AJ003147.1, AP001922.4, AJ251973.1, AL139396.17,AL136304.10, AL136179.15, AC006064.9, Z98752.16, AC003101.1, Z93015.9,AC006038.2, AC011299.3, AC018758.2, AC004840.3, AC016594.6, AL356732.10,AP001710.1, AC005856.1, AC011811.42, AL034429.1, AP003534.1, AL133453.3,AJ246003.1, AC020906.6, AC020716.3, AL121655.1, AC004895.2, AD000090.1,AF235097.1, AC021068.17. HKIXC44 111 716213 1-774 15-788 AL523457,AL528447, AL523456, AI829517, AW149466, AI583221, BF939526, AI421289,BF062158, BF939874, AI279154, AI418427, AI703444, AW131506, BF571573,AI936825, AI089933, AI361161, AW014685, AI536856, BF476644, BE047689,AI369406, AW021011, AI457455, AI302724, AI354478, R61374, AI079090,AA120924, AI362672, AW118437, AW178756, BF447506, H45647, H18233,AW023679, H18271, Z25058, AI361962, AA974813, AW079462, AW089212,H41457, AW970953, AW873883, BE939242, BE151736, AA664017, AA120923,H40869, BE762902, AF176422.1, BC001873.1, AF232239.1, AF151522.1.HKTAB41 112 695732 1-783 15-797 AW269751, BE046932, AI962247, AI652884,AI336991, BF592937, AI632408, BG260037, AI611738, AI784252, AI633419,AI863382, BF343172, AW163834, AI927755, AI500061, AI783997, BG256090,AI470651, AI571909, AI829327, BE535358, AW162189, BF342070, AL036980,BF828567, BE544111, AI886415, BE965031, BF792961, AI590120, AI918655,AI569583, AI288285, AI554821, AW059713, AW148716, AI648684, AL079963,BE047852, AW268122, BE048071, AI569309, AI698401, BE910373, AW148970,BE047737, AW089664, AI784230, BE538997, H89138, AW827289, AI916419,BE895585, AI468872, AI358701, AW105601, AA427700, AI886192, AL041150,AI269862, AL514129, AI345347, AL037582, AL037602, AW131308, AI863321,AW149227, BF727034, AI343059, AI251221, AI349933, BG035511, AI345608,N80094, BG166654, AI922901, AI345253, AW827227, BF527014, BG029053,AI500662, AI348854, AI345471, BG179993, BE965355, AI869377, BG115626,AI679179, AW827106, BF970768, AI590686, AI471361, AI873644, BG031539,AI174394, AI933589, AI635067, AI565128, AV702623, AL036403, AA908294,BG250190, BE620444, BE964812, AI921248, AV743962, AW169604, AL047675,AI282679, BF856017, AI886753, AL121286, BF794018, BE536058, AI801325,BF854113, BG109270, BG165979, AI431424, AI445992, AW029275, AI699011,AI874166, AL036638, AW088903, BG031664, BG120816, BG168696, AL514691,AW268302, BE907440, AW072719, AI589267, BF816037, AI611348, AW059828,BE965724, AW827103, AV710608, BF920893, BF814527, AW118496, AI499986,AW117919, AI826225, AI811785, BF816042, AI681985, AA225339, AW054931,AW196299, AI619502, AI680162, AI478123, AI677796, AI802542, AI352497,AI439717, AI288305, BF672397, AI284131, AW118518, AW023590, AI499285,AI863411, AW983829, AW050578, AW148356, BG249582, AI570807, AI306705,AI824576, AW169653, AW026882, AI470293, AI923370, BG058150, AI312428,AI159837, AI613436, BF812960, BF812938, AI950664, AI537960, BG164558,AI582932, AV727776, BF970652, AL042628, AI520809, AI637748, AV746964,BE789764, AI537303, BG027280, AI521560, AW089350, AI497733, AI433157,AI702073, BF089711, AI569975, BE047732, AW188554, AW183130, AI567582,BF812961, AI500523, AL037454, AI683492, BE874133, AV699198, AW117746,BG179633, AI683173, AI445165, AI963216, AI863082, AW102761, AI564749,AW051088, AI282326, BF814420, AW172723, AI868204, AI633125, AI888522,BF680133, AI887247, AI698391, BG122481, AI869367, AI612885, AI783504,AL036214, AC006451.5, AC007056.4, AC006013.3, AL445528.16, AP000344.1,AC004057.1, AF131216.1, AC007597.3, AC004837.1, AK026504.1, AC006501.5,AL050092.1, AP001731.1, AL389939.1, AL133075.1, Y16645.1, AK026533.1,AL583915.1, Z99495.1, AK026462.1, BC005890.1, AB063070.1, AL512750.1,AK024538.1, AL389982.1, AL122121.1, AL122123.1, AL121916.14, AL157431.1,AL390154.1, AF353396.1, AL137550.1, U39656.1, BC005168.1, AL136805.1,AF078844.1, AL080124.1, AK025209.1, AL110221.1, AL512765.1, AL117435.1,AK026408.1, AL122049.1, AB055374.1, AB047801.1, AK027868.1, AL080159.1,AB060916.1, AK027160.1, AF090903.1, AK027164.1, AK026464.1, AL049452.1,AK000432.1, BC001045.1, AK000486.1, AK025798.1, AB063079.1, AL136864.1,BC008387.1, AL162008.1, AK027096.1, BC002839.1, AK000137.1, AF162270.1,AB055303.1, AL359601.1, AB060887.1, Y14314.1, AL157482.1, AK026593.1,AF146568.1, BC008365.1, AL117432.1, AL137292.1, AL136749.1, AL137476.1,AL512718.1. HLDBG17 113 855953 1-638 15-652 BF002740, AW015349,AW172836, N51711, BE619681, AA620652, AA639043, AA447223, AA648349,AL048032, D62490, BE930019, AI973069, AI370576, AI889304, BF885813,AW975098, BF377527, BF885812, AI370615, Z41325, BF885814, R39086,AA658236, BE708124, AF131793.1. HLDQU79 114 740755 1-1474 15-1488BG256275, BE867624, BE907396, BE855521, BF034422, BF530803, AW959247,BE782005, AI126689, AL121446, AA757065, AW630129, BF768037, BE746763,AA206154, AA460401, AI276320, BF998689, AA295243, BE242732, BG035901,AL040350, BE242810, T86168, BF983867, W05088, AA347337, BG252443,AI133502, AF064093.1. HLDRT09 115 830544 1-707 15-721 AI866557,AA889696, U66673, AI653711, AW130629, AL530677, BF526233, AW468114,BG150565, BE855729, BG255222, AI632354, AL529262, AI672056, AI193721,AI149691, AL048367, AI201831, AI767058, AI364991, AW450832, AW510340,AW275893, AI150164, R49046, AA972284, AI917762, T19369, AL048395,AA954036, BE799697, W45334, AI695488, AW005652, AI867905, AW593521,BE550530, C20962, AW975426, AW772241, BE550612, AA715469, AF202366,BF857142, AI207097, AW205829, AA665913, AW072705, AI275314, AI252147,AI053412, BE042038, AI611493, AW086306, AI225259, AI335447, AI306279,AI336733, AI313009, AW074912, AW075200, AI284547, AI223483, AI340903,AI371626, AI224247, AI249854, AI611505, AI344093, AI613371, AI252683,AI250011, BE049031, AI275343, BE139666, AI311703, AI223583, AW302308,AI307540, AI313289, AI254993, AW073479, AI344172, AI223547, AI306197,BE857864, AI250312, AI251146, AI580534, AW302714, AW302804, AI254415,AI266765, AI305703, AI224293, AI306267, AI613374, AI432751, AI344229,AI053844, AI371955, AI334864, AI053823, AI311600, AI310544, AI580639,BE042235, BE042295, AI311615, BE041253, BE042122, AI305591, AI310294,BE043287, AI224692, AI890550, BE043496, BE041798, AW302103, BE139398,BE139130, BE138588, AW072736, AW301907, AW470468, AI054318, BF718321,AI345502, AI432745, BF718329, AI305392, AA947610, BF055794, AI306075,AI311211, AW664349, AI624279, AL119863, BF904244, AI917252, AI829327,BF672397, BG121222, AI612885, AI280747, BE672647, BG113385, BG168549,AI554245, AA225339, BG163618, AI955866, AI784252, AL514457, AI800453,AI270183, BE785868, BE045182, AI537677, AI274508, BF814541, AL134999,BE018334, BF792961, AV753074, AI564749, AV706744, AI866457, AW020693,AI611738, AI282326, BG036479, BF970768, AW411310, AI270707, AI890507,BG109270, AW880037, AI335426, AI348777, AV682525, AI923989, BG113188,AI866131, AW302965, AA480074, AW673679, AI812015, AI439717, AI569583,AW169653, BG105895, AI934147, AI613436, AW022682, BF872670, AI801544,AI500077, AI610114, AW071417, AI862144, AV657079, AI699857, AW983829,BG030364, BF033296, AW268067, AI621209, AI800433, AL036638, BE879967,AW050850, AI471361, BG029829, AI312428, AV727776, AI869367, BE964614,AW148320, AI569579, AW075413, BE885241, AI308032, AW196105, AL121328,AI344785, F27788, AW073994, AI889953, AI886124, BF793370, AI567612,AI624120, BE905335, BF529088, BE886728, AV734185, AI950664, BF529870,AW020095, AV757362, AI251205, BF885081, AW149227, AI590134, AI497733,AI500659, AI619748, AI824576, BC000559.1, AF070598.1, AK026067.1,AF308472.1, AJ289233.2, AF076775.1, AB039371.1, AB039368.1, AB039369.1,AB063070.1, AB039367.1, AL049314.1, AL442082.1, BC008893.1, AK000323.1,BC004951.1, AK000432.1, AL136892.1, AL080127.1, AK026542.1, BC001967.1,AK024588.1, AK026630.1, AB060825.1, AB055303.1, AB060887.1, AL133016.1,AK024538.1, AL050172.1, AL122050.1, BC008899.1, AK026959.1, AL136844.1,AL133557.1, AL110221.1, AL117583.1, AK025798.1, AK026927.1, AF061943.1,AL512754.1, AL136787.1, AL512718.1, AL137550.1, BC006164.1, AB063046.1,AK025484.1, AB056768.1, AL133565.1, AB049892.1, AK027113.1, AF090943.1,AK026353.1, AL137271.1, AB060908.1, AK027204.1, AL133560.1, AL122093.1,U42766.1, AL122110.1, BC007326.1, AK026528.1, AF218014.1, AK000137.1,AK027200.1, BC007199.1, AK027868.1, AF219137.1, AL512750.1, AB052191.1,Y16645.1, AB050510.1, Z82022.1, AL117460.1, AL049452.1, BC004370.1,AK026744.1, BC001045.1, AF207829.1, BC008488.1, AF056191.1, AK000618.1,AK026629.1, AL137459.1, AK000647.1, AK025084.1, AK025209.1, AB056420.1,AB060916.1, AL136915.1, AL050277.1, AL512689.1, AL117457.1, AL136845.1,AL133606.1, AL137521.1, AL390154.1, AK026532.1, AL050108.1, AL110225.1,AK024524.1, AL110196.1, AJ242859.1, AL162006.1, AL359601.1, AF090900.1,BC008387.1, U80742.1, AL117394.1, AK026534.1, AL050138.1, AL136749.1,AF353396.1, AB055366.1, BC002733.1, BC007021.1, AL136768.1, AF125948.1,AF090896.1, AL080124.1, AK026647.1, BC003683.1, AK026480.1, AK026583.1,AL137560.1, AL359596.1, AB056421.1, AK026855.1, BC004958.1, AL122098.1,BC007198.1, AL117435.1, X72889.1, AB051158.1, AL136786.1, BC008280.1,AK000486.1, AL136789.1, BC003548.1, AF260566.1, AF078844.1, BC008780.1,AB048953.1, AL049430.1, BC003687.1, BC006807.1, AK025414.1, AL512746.1,AB063079.1, AL133014.1, BC008365.1, BC006412.1, AJ012755.1, BC006195.1,AB055315.1, BC008070.1, AK026526.1, AL162008.1, AK026642.1, AK027116.1,AB060863.1, AB055368.1, AK026462.1, AL359615.1, AL137463.1, AK026504.1,AL049300.1, AL137557.1, AB048964.1, AK025391.1, AL050024.1, AB047801.1,AF090903.1, AL050149.1, AL157431.1, AL080137.1, AL133113.1, AF271350.1,AL162002.1, AF230496.1, AB060826.1, AF162270.1, AL050116.1, AK025958.1,AL049464.1, AK025092.1, AB060852.1, AF111847.1, AL353940.1, AF146568.1,AL136586.1, AL050393.1, S61953.1, AB019565.1, AL080060.1, BC008382.1,AF097996.1, BC008417.1, AL133640.1, AK026651.1, AF217987.1, AK025254.1,AK026593.1, AL359620.1, BC005890.1, AK025906.1, AK025339.1, AB056427.1,AK026164.1, AL512733.1, AB048954.1, AK027164.1, AK000391.1, AB060214.1,AL110280.1, AF026816.2, X82434.1, AL122049.1, AL133093.1, BC002839.1,AL512684.1, AB047904.1, BC006440.1, AL359583.1, AL117585.1, AK026600.1,AK025383.1, AF125949.1, AL050146.1, BC004556.1, AL136799.1, AF061573.2,AL122121.1, AL136805.1, AF091084.1, AL049466.1, AL136928.1, AL162083.1,AF090934.1, AK027096.1, AK026086.1, AK025967.1, AK026597.1, BC002643.1.HLHAP05 116 638476 1-1828 15-1842 AW963016, AW979070, AA554869,AA828610, C14699, AA359181, C15123, AI380617, AW303196, AW301350,AW023111, AW974639, AI798545, AA359849, AV711430, BE252421, BG222813,BF974349, BG236628, BF804385, AI246796, BF918155, AV711465, BE180633,AW327868, BE301584, BF879045, BF965775, AA574442, AI253987, AW410784,C15415, BF761328, AI357823, BE676019, AV738383, AW270258, AW167330,AA610509, AI188390, BG029224, AV759972, AL117335.26, AL109976.23,AC009087.4, AL136081.10, AL021579.1, AF064861.1, AC079684.16,AL163279.2, AL136000.4, AC006014.2, AC005067.2, AL049839.3, AL035587.5,AC008569.6, AL513131.1, U89335.1, AC008771.4, AC005052.2, AC073136.6,AC003104.1, AL117336.22, AL031730.1, AC022515.5, AC009570.13,AC010328.4, AL049776.3, AL135749.3, Z85986.1, AC002369.1, AC007201.1,L44140.1, AL133545.10, AC011450.4, AC013726.7, AL034405.16, Z84469.1,AL139099.2, AL136305.14, AC020908.6, AC005291.1, AC008622.5, AC004647.1,AL158040.13, AC018636.4, AC008625.5, AC005488.2, AL050307.13,AC083863.2, AC007969.3, AC016602.6, AC002316.1, AC010126.3, AL359235.3,AC006480.3, AC004819.1, AP001748.1, AC006157.2, AL121969.12, AC003093.1,AC011236.8, AC009362.8, AC018648.5, AP000924.6, AC005261.1, AC004520.1,AP001705.1, AC008280.4, U47924.1, AC018695.6, AC004000.1, AL049646.19,AC002425.1, AC011005.7, AL359711.18, Z85987.13, AL132659.10, AC004953.1,AC006329.5, AC016594.6, AC011465.4, AC073321.4, AP000240.1, AC007308.13,U95742.1, Z97056.1, AL049761.11, AL391241.21, AP002852.3, AC025679.4,AP000424.3, AP000096.1, AL031311.1, AL034420.16, AC005098.2, AC009086.5,AC026464.6, AC002350.1, U91318.1, AC007664.12, AL020995.14, AL354813.31,AC083866.2, AC004797.1, AC004791.1, AC002504.1, AC005722.1, AC022211.5,AC009068.10, AC022405.5, AC005932.1, AC025457.5, AF318296.1, AC005077.5,AL161670.4, AC004815.2, AC027129.5, AC012170.6, AC011894.3, AL121586.31,AF287262.1, AC006530.4, AC022415.5, AL162293.22, AL117352.12,AL121891.22, AC007216.2, AL034451.26, AC009244.24, Z97985.16,AC006006.2, AC011247.10, AL132713.11, AL133246.2, AL135818.3,AJ400877.1, AC004098.1, AC004922.2, AP001670.1, AC010618.7, AC009137.6,AC011551.3, AC002470.17, AC011737.10, AL353668.18, AC079361.17,AC007421.12, AC005520.2, AC005082.3, AC005099.1, AL035659.22,AL445928.8, AL136300.22, AF243527.1, AC005940.3, AC019205.4, AC024561.4,AC004655.1, AC005562.1, AC004656.1, AC072061.8, AC016995.4, AC015853.8,AC004222.1, AC005531.1, AL354816.5, AL157372.18, AC006483.3, AF168787.1,AC012151.13, AL109935.39, AC006211.1, AC004128.1, AL035088.1,AC005952.1, AC011453.4, AC004648.1, AL133228.18, AC010913.9,AC007371.16, AC007030.3, AL121972.17, Z95152.1, AC000134.14, AC034198.6,AC007690.11, AL117382.28, AP001630.1, AL162430.15, AC006452.4,AL589723.7, AL009181.1, AL121992.24, AL132768.15, AL445490.6,AC008072.3, AC007220.4, AL132640.4, AP000210.1, AP000132.1, AC068724.7,AC004702.1, AL359792.3, AC004216.1, AC006509.15, AL049636.22,AC011816.17, AC008397.7, AC020916.7, AC010326.6, AL162464.5, AC005378.2,AC069262.24, AL031905.7, AF288742.1. HLHCS23 117 560663 1-1413 15-1427AL512506.8. HLIBO72 118 88343 1-1754 15-1768 AW364017, AV726728,BF035681, AA169752, AW364018, AW473802, AI983855, AI925556, AW069100,BE677197, BF382750, BF590308, AW970436, AW069481, AI341115, AA622018,AI167674, AI335907, AI377478, BE677196, AI352114, AA373289, AA826793,AA443946, AA431454, AA768408, AI274003, BF727025, AA630606, AW364013,AA132208, AW574586, AA621404, N54466, AA593091, BG166649, BF883778,BF882969, AA127838, AI695553, BF371992, BF793125, AA807643, BF965857,BF739818, BE074542, H02646, BE395704, BG249993, AV764523, BG249406,BF832747, AW964084, AW673241, AW969921, AW276827, AW969698, AW969694,BF698559, BF337291, BE350475, AI570261, AV759382, AW972871, AW731867,AI289067, AV764398, F36273, AI061334, AL046409, AI679782, AI619997,AA177061, AW088202, AW975425, AW419262, AI085719, W79504, AW472872,AW029038, AI653636, AI471481, BE047069, AI688846, AI053672, AW301350,AI904894, AI341664, AI284640, AW303196, AW193432, AW406162, AI471543,AA843450, AI801600, AL042420, AW502975, AV762395, BF680805, BF851403,BF854876, AI375710, AI431240, AW406447, AV763988, AI537955, AI963720,BF939954, AV713741, AI298710, AV735370, AI379719, AW162049, AW276817,AI653886, AI929531, BE540527, AI962050, AW517377, AI365988, AI344844,AI357288, AW274349, AW008317, AW769399, AL120502, AI368745, AW261871,AI339850, AW339568, AI017415, AW630298, BE872393, AV740801, AI434695,BF668217, AA649642, AV763540, AW338086, BG169853, AA127353, BG249643,AI053790, AV710066, AW511743, AA581903, AA577906, BG118285, AI431303,AI471534, AV760937, AI143242, BF794230, AV763633, AW193265, AI281697,AA350859, BF698579, AA610491, AV764530, AI446601, AI282832, BF210720,AI951863, AI590689, AI590958, AI951889, AU158383, AV760624, BF840326,AW833862, AA522942, AI281881, AI732186, AL038785, AI801591, AW501386,BG036665, AW576391, BE677379, AW970865, AA446657, AI334443, BC007829.1,AB014733.1, AC008383.8, AF140225.1, AL449363.12, AP000348.1, AC004263.1,Z86061.1, AC007151.2, AC087239.18, Z82244.1, AC011475.6, AC009996.7,AC018828.3, AC022383.3, U02532.1, AF015160.1, AP000901.5, AC005280.3,AC079753.7, AC006277.1, AC008764.7, AL022322.1, AL354932.26, S75201.1,AC012442.7, AL049776.3, AL121891.22, AF015158.1, AC087071.2, AF015156.1,AC004672.1, AC009086.5, AC004898.3, AC005104.1, U12582.1, AC024561.4,AC004824.3, AC005520.2, AL031320.6, AC007676.19, AF015151.1, AC073273.9,U12584.1, AC002984.1, AF015167.1, D83989.1, AC011485.6, AL031672.13,AC006211.1, AC005234.1, U47924.1, AC011480.3, AC073517.5, AL122035.6,AC007782.20, AL121897.32, U57005.1, AC006329.5, AC004596.1, AC005484.2,AL161756.6, U63721.1, AF077058.1, AP001666.1, AF015162.1, AF015148.1,AL162891.4, AP002851.2, U57007.1, AC004797.1, S56967.1, Z68284.1,U12580.1, AC020658.6, AB053170.1, AC007686.5, AL031985.10, AC011443.6,AF207550.1, AL008629.9, AC006479.2, AL365364.19, X55931.1, AL031005.1,AL109935.39, AP001729.1, U18391.1, U18394.1, AP000719.4, AC010679.6,AL035658.7, AC005282.4, AL354935.23, AC035150.1, AC027319.5, AC021382.6,AC018636.4, AC021019.5, Z99716.4, X54180.1, AF251315.1, AC011742.3,AL139327.18, AL022302.10, AL355499.15, AL136418.4, AL139054.1,AL445217.3, AF015155.1, AL035659.22, AC009796.6, M87916.1, AC004840.3,AF042090.1, AC005231.2, M37551.1, AC005664.2, AL139251.13, AL136110.17,AL121581.41, AP000311.1, AC004589.1, AC068533.7, AC016898.6, AC002985.1,AF015157.1, X55925.1, X54177.1, AL353580.7, AC005755.1, AC005778.1,AL122004.17, AC002491.1, U18393.1, AC069255.18, AL590762.1, AC000358.1,AF015165.1, AC034200.6, AL590964.8, AC005911.6, U18387.1, AC010404.5,AP001685.1, AC005632.2, AC007899.3, AC009131.6, AB045361.1, AC012087.10,M87919.1, AC073258.9, AC007316.4, AC084882.2, AC007731.14, Z97054.1,AC008744.6, AL133402.10, AC007240.2, X55926.1, AL356481.16, Z93023.1,AC005500.2, AC022493.12, AC006157.2, X53550.1, AC008622.5, AC020906.6,AC021752.5, AL031729.16, AB037745.1, AC017079.5, AC008155.9, AP001718.1,AC006483.3, BC001368.1, AL163282.2, AC008795.6, AL136365.9, AF283320.1,U12581.1, AL157373.23, AC003007.1, AL031685.18, AC004002.1, AL133480.9,AC005409.1, AL021878.1, U57008.1, AC006476.3, AF095855.1, X54176.1,AL022476.2, AC005531.1, AC083863.2, AL031123.14, U18398.1, AC016772.8,U62317.2, X75335.1, AL110115.38, AC010000.5, AC011472.7, AC007363.3,AC008079.23, AL035587.5, AC006433.18, U18395.1, AL133370.4, AC016939.8,AC023114.5, AC074338.1, AC005324.1, AC018751.30, AC010422.7, AC006213.1,AC011455.6, AL133232.15, AC010319.7, AP001172.1, AC022392.4, AF015170.1,AC013604.9, AC010677.4, AL031276.1, AL121845.20, AP000555.1,AL035668.15, AP000161.1, AC008033.8, AC009122.8, AC020915.6, U67827.1,AL135924.11, AF176815.1, AC004773.1, AC009161.12, AL121944.14, X54175.1,X54181.1, U57009.1, AD000092.1, AC083871.2, AC005497.9, AL139039.17,AC004224.1, N76577, AA535949, D20477. 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AF369701.1,AL157479.1, AF230496.1, AK026462.1, AK026356.1. HLYDF73 124 566869 1-61215-626 AC009753.5. HLYGE16 125 651339 1-738 15-752 AW469203, BF820842,BE218294, AW196671, BF447223, AI696980, AW236972, AI027666, BF798334,BF807954, BE217850, T59291, AI267964, R44968, AW444500, AW295686,AW291949, AI928514, AI823933, AU153630, AI139764, BE005097, AI948643,BF108749, AI126466, AW242784, R49472, AU160792, AW273139, AI273589,AW589378, AI274894, BF448101, AW510475, AI302181, AI400517, BE550344,AI365030, H18516, AI206723, F09161, F09171, AI696176, AI992327, F09169,AW051573, AA847131, R86756, AU148421, AU154040, AI421825, AU159186,AI146780, AI910733, AA868280, AA722823, BE504675, AI739531, AU152829,AA868452, AI911876, BE552250, AI168680, AI954643, AI913116, AW237207,BE502531, AI142459, D80575, AW002567, BF939794, D80957, AA702863,BF591908, AA455456, AI015316, AA922953, AV645338, AA514480, AI420243,R86981, AI420270, T59250, BF508779, R60233, R51570, AI580357, W86599,AA417873, AA085431, AA227559, AA852691, H57046, BF845379, AA192359,AI580716, AA455455, AA776815, AI140464, AA075296, BE300079, R27183,AA814809, AW105331, AA024748, D81100, BE620885, BF845381, R27182,BF912382, BE904044, BE904041, BE881261, BE965135, AI631590, BE551572,AI656791, AA282050, BG055430, AA937231, AC025594.5, BC009221.1,AK022910.1. HLYGY91 126 658703 1-626 15-640 AW294783, BE502344,BE222441, AI082255, AI031661, AI701563, BF431032, AW340159, AI250886,AA164268, AA113365, AW195764, AA813476, AI382168, AW044458, AI802164,AI149406, BF196258, AU155794, AA479123, AI167291, AI436306, AI224847,AI417116, AI709346, AI669258, AW772002, AA844518, AI282711, AI279738,AW195230, AW959069, BF002627, AI560087, AI286319, AI474555, AI092394,AA479124, AA243709, AI468637, AW991244, AA508073, AA243826, AI468739,T62160, AW975954, T61934, BE707630, BE169617, BF747189, BE832694,AA746981, AA328991, AK023448.1. HMCFH60 127 654853 1-429 15-443BG029413, AW410249, AL120205, AL527305, AI754933, AW410004, AW411240,BE207947, AI348361, BG254821, AV717836, AI282565, AW015954, AI860745,BF970512, AI279557, BG250088, AI301063, AI887607, AW675703, AI277972,AI751711, AI610303, AW168266, AI954092, AW732241, AI199700, AI310726,AA533655, AI219656, BE047165, AI828679, AI829142, AI874208, AI741030,AI445423, AW339140, AW872712, AW872550, AI310725, BE675720, AW276596,BE049270, AA526998, AI300518, AI805844, AI814591, AA832328, AI927014,AA461097, AW337251, BE393698, AI453250, AW009901, AA522451, AI970703,AI147456, AI799656, AI866733, AI092937, AA526185, AI721118, AI017038,AI613235, AI339100, AW148657, AI538694, AW008035, AW269978, AI818220,AW130721, AI369774, AW778916, AA508660, AI285115, AW118526, AA280728,AI803837, AI078009, AI249388, AW274402, AA449775, AI741564, AI983830,AI953077, AI283484, W94943, AI186921, AA573897, AI078388, AA670351,AI423558, AW273429, AA745775, BE727124, AI591031, BF732731, AA903469,H98073, BF973696, AA628743, AW270071, AA987523, N91829, AI144428,AI081865, BG057107, BE797291, BE798645, AW899935, N34882, BG057959,AA065282, BE910046, W68425, AA132945, H26397, AA130713, AI535963,AA526103, BF436402, BF924840, AW189969, AA813305, F25776, R59097,BF793976, AW071554, AA102712, AL527475, W90665, AL533663, AL523124,AI246999, AW194200, AA677814, AW150820, AA004278, AL533350, AI983597,H25535, AI282522, BF941561, BE617576, BE613255, BF689583, AL521962,BF568937, R56834, AL524248, AI299507, AA805472, H46569, AW004802,BF828652, AA580297, AI364662, AA703237, AL521083, R56835, AA628330,HF570271, BE877417, AI365012, H56058, AA229754, AA229480, AA302484,AI918967, AI553849, AA373811, BF688841, AA853526, AI560300, AW470964,AA682774, BE858486, BF914567, AA496495, AI950742, R56673, AA526614,AA496620, R96820, AI972733, AA868647, AA644220, AA447147, AA228723,BG015338, AA887190, AA229233, AI690364, T51235, AW075387, AA953331,BG112305, AA713800, AI094450, H61569, BF375945, AA449063, AI026692,AA159983, BF914242, T73441, AI720505, BF336367, F31462, AI827198,AW772776, AA614196, AI300639, F18178, R10734, BF336341, BE548560,AA858412, BF912964, AA229962, AA872093, AI015741, AI051521, AI203695,AA978132, AA988865, AA365973, BF948395, AI690503, W68523, AA229458,Z38471, AW262508, AA736839, BF690492, BE181244, AA007293, BE122672,AW182880, BF947488, AW771037, AI350873, AA557419, BG016041, AW515865,AV697048, R56672, T24559, BF183570, AA923506, AF189289.1, BC000702.1,AF176006.3, AF192559.3, AF151822.1, AK022783.1, AF090943.1, AL512733.1,BC005402.1, BC006091.1, AL359583.1, AK027129.1, AK025414.1, BC007462.1,BC001967.1, AB060832.1, BC008842.1, AK025435.1, AK025113.1, M85165.1,AK027103.1, AL353940.1, BC004951.1, AL050172.1, AL389947.1, AF056191.1,AK027082.1, BC003651.1, AK027136.1, AL389935.1, BC009398.1, AL137530.1,BC002370.1, Z37987.1, AK000653.1, AK027102.1, AF245044.1, AL080146.1,BC008836.1, BC004290.1, AL137459.1, AB056372.1, AL137548.1, AL080162.1,AL137533.1, AL137657.1, AF232009.1, AB063100.1, AL355713.1, AB047878.1,AK026542.1, BC008780.1, AK024594.1, BC009395.1, BC004925.1, BC006196.1,AF261134.1, AF100781.1, BC001778.1, BC004945.1, AL137271.1, AB056421.1,AK024974.1, AL080234.1, BC007567.1, BC004264.1, BC004156.1, AK026885.1,AF352728.1, AL050155.1, BC004899.1, BC002471.1, AK026494.1, AF090900.1,BC002476.1, AB052191.1, AL049447.1, AB060229.1, BC003587.1, BC007926.1,X59812.1, BC000054.1, AL136586.1, AL137550.1, AL110159.1, AF026816.2,Y14040.1, AK026528.1, AK026480.1, BC008591.1, AL049382.1, BC002357.1,AL049314.1, BC004362.1, AF177336.1, AL157464.1, M85164.1, AL117460.1,AB046642.1, AL137281.1, AL137529.1, AF252872.1, AF260566.1, U73682.1,AL110280.1, BC002733.1, AL133084.1, BC008899.1, AK026959.1, AK027173.1,BC001964.1, AJ010277.1, AL136805.1, S76508.1, BC001470.1, AK026649.1,AL117587.1, BC003591.1, AK025099.1, AB060897.1, AK025092.1, AL512718.1,BC003548.1, AK026608.1, BC003052.1, AK026626.1, AL136844.1, AK027144.1,AB063046.1, AL353952.1, AL117435.1, AL133623.1, AL162002.1, BC002399.1,AL049464.1, AL359622.1, BC001166.1, BC002752.1, BC007280.1, BC008364.1,BC001236.1, AL122050.1, AB060837.1, BC006159.1, M86826.1, AB051158.1,AB044547.1, AL137711.1, AB060888.1, AL110158.1, AF061795.1, AF151685.1,AF274348.1, AF274347.1, AK025484.1, AF044323.1, AB062978.1, AL137479.1,BC005070.1, BC000077.1, AL122110.1, BC003658.1, BC003410.1, BC003637.1,BC004923.1, X82434.1, AF353396.1, BC007206.1, BC002816.1, BC008649.1,AK026583.1, AB060873.1, AL110296.1, AB063074.1, AL117416.1, AF217987.1,AK026784.1, AL390184.1, AF271781.1, AL137554.1, AK025798.1, AK025239.1,AB056809.1, AL136893.1, AL133016.1, BC008840.1, AL136748.1, U42766.1,AL136787.1, S77771.1, X53587.1, BC007499.1, AF090923.1, AL122104.1,AK027193.1, AK027213.1, AK025254.1, AL122118.1, BC001082.1, AL080060.1,BC005825.1, AB050407.1, BC008195.1, BC007255.1, AB060863.1, BC007456.1,AB050421.1, BC001045.1, BC006458.1, AB060825.1, BC004310.1, BC003602.1,AK026534.1, AL049996.1, AL359624.1, U70981.1, AK000418.1, AK024533.1,AL117438.1, BC004196.1, BC008686.1, AB050510.1, BC008387.1, AB055374.1,AB060916.1, U55017.1, BC002631.1, BC000090.1, X67688.1, BC005165.1,AK000257.1, AL110221.1, BC000570.1, AJ296345.1, AL050393.1, AK026631.1,U88966.1, AK026506.1, AK026593.1, BC004960.1, BC000778.1, AL117648.1,AK000614.1, AL137429.1, AL133637.1, BC006147.1, Y16645.1, BC002539.1.HMDAB29 128 584789 1-1176 15-1190 AV756491, AA714011, T74524, AW970571,AI284543, AA847499, H07953, BE139139, AI250552, BE676912, AI251284,AI251034, AI251203, AL042373, AI254770, BG169404, AW504485, AI223626,BE062159, AI755214, AW303098, AW500684, AI754567, AI053398, AI792575,AI754105, AI278972, AW576251, BE138594, BE138387, AW023111, BE315483,AI923052, AA449997, AW973992, AV762354, AW969667, AA829036, AA937809,BF725844, BE150796, BF832074, AW973757, BE968744, AI254779, AA773463,AI085242, AL119247, AI962030, AV763550, AW467607, BE674881, AV649707,AI674840, AA630854, AW167330, AV710482, AW265342, AV762975, AV649853,BE256101, AA315361, AW850517, AA828834, AW958962, AA828054, AI687343,AW963463, BG012020, BF854170, T11828, AW270771, AA621865, AI963720,AW502237, AV733437, AV723671, AA127426, AI732151, AL042667, AL042670,AI745151, AI249853, BE160727, AV762633, AW965008, AL119921, AI620992,AW969831, AA809546, BG110480, AA680243, AA618316, BG152386, BG115297,AW471332, BF950533, AI627614, AA524616, AA828637, AI524193, AW500161,AV763540, AV738383, AI613389, AI890971, AI279417, BG105498, BF724372,AL524675, AW970064, AA683069, AW265688, BF868994, AI049676, BG026977,AI457389, AW193265, AA503019, AI334248, AI440117, AA651639, AK025218.1,AC007308.13, AC002470.17, AC004824.3, AC010271.6, AL031283.26,AC009412.6, AC005399.19, AL136305.14, AC010913.9, AL135927.14,AC007227.3, AC011455.6, AC008670.4, AC016602.6, AC006337.4, AP001718.1,AL049839.3, AL033524.11, AC006038.2, AF200465.1, AC005200.1, AC005233.2,AL109804.41, AF051976.2, AC010319.7, AF243527.1, AF207550.1,AL121601.13, AC005077.5, AL133367.4, AC005740.1, AL117333.26,AC005324.1, AC004821.3, AC011895.4, AC007956.5, AL137849.13,AC006433.18, AC007991.7, AL139415.10, AC022211.5, AL024498.12,AL159997.14, AC011740.7, AL161731.20, AC016995.4, AC005529.7,AC004953.1, AC007722.9, AC006330.5, AC026464.6, AL359986.15,AL121895.26, AL031228.1, AL031276.1, AC006965.3, AC004134.1,AL050350.14, AC022148.5, AC004408.1, AC008755.6, AL050349.27,AL109806.22, AL133240.3, AP000963.2, AL034379.8, AL109843.25,AP001709.1, AJ277546.2, AL121972.17, AL031670.6, AP002852.3, AB038653.1,AF045555.1, AL031311.1, AC003080.1, AL020997.1, AL121808.4, AP000117.1,AC004796.2, AL354707.17, AC020552.4, AL122020.5, AC009131.6, AC008752.6,AL158817.11, AC009488.5, Z98884.11, Z83826.12, U63721.1, AL049776.3,U62292.1, AP000298.1, AC005484.2, AL132768.15, AL161747.5, AC018636.4,AL158207.15, AL137119.26, AC005409.1, AC012372.4, AL449209.2,AC008440.8, AC074013.5, AE006464.1, AC004813.2, AC009032.7, AC007676.19,AC018462.4, Z98304.1, AC011495.6, AL359092.14, AC008753.8, AC005527.3,AL034417.14, AL121753.30, AL033527.26, AL109921.21, AL132640.4,AC009068.10, Z85996.1, AL035684.25, AF317635.1, AP000424.3, AC000025.2,AC008521.5, AL158040.13, AC019171.4, AC006952.6, AC004024.2,AL031847.17, AJ011930.1, AC011479.6, AL163300.2, AL109976.23,AC004707.1, AC006121.1, AF053356.1, AL022316.2, AL121594.6, AL160165.17,AP000429.3, Z98946.15, AC005236.4, AC006064.9, AC010608.6, AL035411.27,AL365444.11, AL031428.9, AC010422.7, AC003682.1, AC005921.3,AL109801.13, AL354668.13, AL137139.9, AC005971.5, Z93017.6, AP002453.3,Z82215.1, AC008050.6, AL049694.9, AL022312.7, AC005071.2, AF196970.1,AL133163.2, AL451075.15, AC005086.2, AL035071.17, AC004156.1,AL136295.3, AF196779.1, AC022382.3, AL391280.15, AC020898.5, AC006057.5,AC004659.1, AC012614.6, AL121712.27, AL136137.15, AC005058.1,AP001711.1, AC005995.3, Z82206.1, AL139343.9, AP000925.5, AP000044.1,AP000112.1, D84401.1, AL096791.12, AP001781.4, AC004826.3, AL158052.10,AC005225.2, AC004975.2, AC004797.1, AC007546.5, AC083884.6, AL355517.12,AC011465.4, AL109935.39, AL132712.4, AL021808.1, AP000193.1,AC023798.16, AC005914.1, AC005229.1, AL158830.17, AC004253.1,AC005056.2, AL391259.15, AC008745.6, AC008760.6, AC072052.6,AC019195.10, AC005620.1, AP001670.1, AP001748.1, AC034200.6, AC004494.1,AC004883.2, AL121936.17, AC009086.5, AC004084.1, AC005907.1, AC003043.1,AL109936.10, AL357519.19, AC004832.3, AC007435.12, AP000501.1, U96629.1,AL137229.4, Z84469.1, AL132777.4, AC008895.7, Z83840.7, AC005274.1,AC005412.6, AC025262.27, AC008649.6, AL391833.10, AC009269.6,AC015651.18, AC011494.2, AL161665.5, AC005332.1, AC011737.10,AP000796.4, AC008687.4. HMDAD44 129 566854 1-1190 15-1204 BF574085,R12644. HMEDI90 130 840077 1-2262 15-2276 BF951698, AW956936, H29379,T66089, AA057405, AW134660, AA057093, AA917450, AL133995, AI299437,AI002692, H18042, R19493, T09261, F11783, F11794, T65008, T09262,R43839, N78357, H29290, AL035633.18, AF263308.1, AF263309.1, AF263310.1,AF263307.1, AF263306.1, AF263305.1. HMICI80 133 827318 1-1758 15-1772AW206437, AI681626, AW590679, AW964447, BG153402, AI457162, AA773037,R53264, R56435, N51755, BF445824, R52470, BF223487, R13042, R40426,R52471, R15858, AI277346, T90387, R35946, T10284, AA194178, R53265,AI267524, T31140, R18993, AA318910, T83131, H05600, T10285, AA194177,R44879, R56436, Z45173, Z41270, Z45583, T31222, H12961, AA679784,AC008790.6, AC008852.5. HMTAB77 135 847411 1-3825 15-3839 AU133217,AL515424, AU117140, AU142384, BG033833, BE876803, AU139465, BG259851,BE743306, BG167796, AW473531, AU135959, BE875637, BG260336, BG107108,AW580231, BG179511, BE888606, BE887292, BG027450, BF671771, AU119885,AW238825, AI689392, BF575632, BF794737, BF791887, AU117158, AI969513,AU136366, AV752386, AA577695, BF347777, AU127278, AL046713, BG036892,BE539387, BE888461, BF035474, AU135160, BG107285, BG025131, AL039354,BF061987, BF812543, BG031453, BF212314, BE734936, BF981318, BG259074,AW957785, AW851018, BE552121, BF819996, AW379372, BE835355, AL039548,BG032762, BF693254, BE893099, BE439886, BF209896, BF207817, BE466166,AW965646, AU138546, AW814786, AU144064, BE888383, BE889498, BF688672,AI338724, BF514065, BF528934, AL040257, BE568710, BF790899, BF790348,BE969916, AU151881, BF381749, AI753682, BE537675, BF103706, BF038173,AA927334, BF240276, BF242051, BE835432, AI742904, N20178, AW966689,AW963156, BF382259, BE567450, AW369137, BF920929, BF750387, AA313265,AA196578, BF693176, BF744444, BE961188, BE280960, BF814166, AL048800,BF669614, BF695646, BF573281, AA584433, BF747979, AW205552, BF930968,BF210307, BE967604, AV758139, AW075512, BF229128, AL041181, BF931659,BG014272, BG032249, BF696371, BF242624, BE841199, BF904837, AW297463,BE537740, R70619, AW957862, BF789995, BE889296, AW293263, BF934769,AW814722, BF247682, AW517759, AA076256, AI580344, AW369831, BF965679,AI917185, AI348555, BE089815, BF742017, AA579344, BF930639, AA578603,N29079, BF750787, AA747403, AA649704, BF102774, R80337, BF674705,BF688897, AV747890, BF210080, AI281795, AA326479, BF028979, H11175,D82206, AA642754, AA355742, D82173, AA326164, BF229913, AL515423,AA363512, BF238375, BE818113, BF672447, BF977594, AW075837, BE893554,BE818095, BE736387, BF742025, AW576881, BF692010, BF820629, AA344537,BE001659, R60858, AV738050, AA650232, AA808866, BF375716, BE972715,BE818049, BE172915, R22704, AA133820, R13289, BG255786, AA301326,N57164, BE818060, BF212867, AA083989, AL046786, BF348022, AA092609,H06323, BE167529, H87922, AA654758, BF215056, W26917, BE895957,AA167156, AW821022, BF901255, T05303, BE088453, BE813024, BE818048,AA363584, H93588, AI928366, H05331, D58857, BF245942, BG235926,BF692607, AU077250, R66345, AA360920, F07286, BE172376, D82200,BF693404, BE081882, R81874, BE896503, BE936475, AW607901, AA454112,AW999261, BE936455, AW383272, BE818043, C16797, BG110805, BF031668,N88563, AW074610, AA384710, D53920, AB018266.1, AK001388.1, AF117236.1,M63483.1, AY007157.1, AL159986.21, AJ224169.1, AJ224166.1, AC024094.28,AL117541.1. HMUAE26 136 747403 1-1986 15-2000 AL523203, AL515749,BE614404, AL515748, BF688628, BE613791, BF976568, BF570015, BE909508,BE907377, BF038761, BG177795, AW405815, AL528809, AA622413, AI362259,AW083964, BF061057, AW813200, AL524973, AI636779, AI097057, AI091346,AA350763, AW003428, AI422009, AI272936, AA102665, AI248453, AA101283,BG178886, AI435624, AW601020, AW813261, BG056509, AW117686, R72555,AW813202, AL528808, AI811322, R73352, AA622414, BE247259, BE703295,AI400034, AA484496, AI356550, AA258572, AA989154, BF797135, R72878,AA350762, T16127, AI699249, AI433994, AI206909, AI968946, AW449847,AW403875, AA884151, AW087452, AA188566, BF350716, AW272969, AW797619,AA188728, BE246100, AW797628, AI432030, AW188539, AI452405, AW813203,AW150511, BF726894, BE621810, BG168441, BG025417, AI432644, BE910738,BG123011, AW968355, AI432653, AW827175, AI623302, BG107986, AI432666,BG168645, AI431307, AI431316, BG115242, AL045327, BE621893; AL047163,BF984267, AW081103, BG117025, BG258222, BG167818, BF984992, BE621811,BG253641, AW858522, AV702117, AL042898, BE614378, AW961253, AI431238,AW772685, AI890907, AL134524, AI859991, AV756413, AV661704, AV705341,AV702833, AI872423, AW957058, AV704955, BF726868, BF726234, AW968356,AV756256, AV701560, AV655280, AV704182, AV708704, BF569517, AV758603,AV755589, AV727807, AW972093, AV655425, BF970652, AV682503, AW968729,AL042787, AI431323, BG168646, AV656478, AV689111, AV708834, AV757189,AV682038, AV701620, AV654896, AI432654, AV728806, AV707024, AV693523,AV733869, AV725920, AV659322, AV692691, AV701914, AV712476, BF345060,AV733387, AV707753, AV704934, AV706721, AV755335, AV696106, AV697196,AL042729, AV699197, AI431321, AV728733, AL045328, AI538850, BG259587,AW971740, AV726738, AW956474, AV685966, BG113493, AV757292, AV701707,AL047675, AV727029, AI866469, AV708438, AV702516, AV728518, AL515195,AV728576, AV724741, AV728157, AV709604, AV709314, AI432650, AV708381,AV655096, BG113712, AV723132, AL046356, AV733917, AI860003, AV703168,BF796402, AV703970, AV726259, AV707792, AV659536, BF795712, BG257535,AL119319, BG110517, BG029667, AV709580, AV728670, AV695545, AI633125,BG252929, AV702427, AV682776, AV726624, AW955613, BE897632, AV729451,AI431230, AV651955, AV704269, AV727799, AL040207, AV760695, BF811793,AV709660, AV705384, AV729220, BF726322, AV708893, BG116926, AV733299,AV682138, AV654908, AV684604, BE672759, AV703169, AV711327, AV705159,BE885490, AV705693, AV757448, AV701881, AV709935, AV703495, AV693527,AI866786, AB037108.1, AL133049.1, AF090903.1, BC003684.1, AL162083.1,AL122049.1, AJ299431.1, AF183393.1, AL050149.1, AK026506.1, X82434.1,Z82022.1, AL137529.1, Y14314.1, AL137533.1, AF026816.2, AK025857.1,AK026744.1, AL137480.1, AF106862.1, AK000418.1, BC008719.1, BC004925.1,L19437.2, AL512705.1, AL512746.1, AB062938.1, BC005678.1, AB056809.1,AL136784.1, AK026462.1, AL137271.1, BC009033.1, AK027096.1, AL512684.1,BC008485.1, BC003122.1, AL080159.1, AB048954.1, AL136825.1, BC004556.1,AL080057.1, AL359941.1, BC009026.1, BC004349.1, AF218014.1, AF225424.1,AL049430.1, AL137550.1, AL353940.1, BC006195.1, AL133568.1, AL162062.1,AL389939.1, AL117463.1, BC005168.1, Z37987.1, AL137488.1, AL080148.1,AF104032.1, AF271350.1, AK026408.1, AK025391.1, AL117460.1, AL136763.1,AF090901.1, AB049892.1, AL512750.1, AL137478.1, AF090934.1, AK025339.1,BC002343.1, BC006494.1, AK027204.1, AK000250.1, AB047904.1, AF260566.1,AK000323.1, U38847.1, D83032.1, BC000725.1, AL050277.1, AL137283.1,AB048953.1, AL162003.1, AL390154.1, AK026642.1, AB060873.1, BC006103.1,AL353957.1, AK000212.1, AK024538.1, AL136892.1, AL117435.1, AL122110.1,AL136615.1, AK026528.1, BC008899.1, AL133640.1, AK026959.1, AL049452.1,AL133053.1, AB056420.1, AK026534.1, AY033593.1, AL080074.1, AK026855.1,AF217966.1, AF217987.1, AL110221.1, AL133075.1, AF262032.1, AK026927.1,X99717.1, AL136845.1, AL133072.1, AL389982.1, AF061573.2, AJ012755.1,AL133560.1, AK000614.1, BC002425.1, AB060826.1, AL049938.1, AK026480.1,AL133080.1, AB055315.1, AK025414.1, AL512733.1, AK027213.1, AB048975.1,AL133077.1, AL050146.1, U80742.1, AL137292.1, AL110280.1, AL050366.1,AK026593.1, AF348209.1, AB055361.1, AK026464.1, AK024588.1, BC004951.1,AF210052.1, AB060863.1, AB063088.1, AK000083.1, AK025632.1, AL359601.1,BC008417.1, AL157482.1, AL110225.1, AL117394.1, AL136882.1, AL136805.1,AF081195.1, AK026630.1, BC008488.1, AL122050.1, AF162270.1, AL137560.1,AL136844.1, BC001964.1, AL137538.1, AK027164.1, AB060852.1, AB055303.1,AB055368.1, AB060887.1, AL117457.1, AL389935.1, AK026542.1, AK025889.1,AB060912.1, AL049283.1, AK026164.1, AF143723.1, AK027146.1, AL122100.1,AL136893.1, AL023657.1, AK026434.1, AL050138.1, AL050393.1, S78214.1,BC002733.1, X98834.1, AF227198.1, AF230496.1, AF285167.1, AL080124.1,AL162002.1, AL133067.1, AL512719.1, AK000432.1, AB050410.1, AB048919.1,AB056421.1, AB052191.1, AK025084.1, AK026762.1, AL137521.1, AL133665.1,AL359618.1, AK027868.1, AF111112.1, AK027114.1, AL137526.1, AK024992.1,Y16645.1, AL050024.1, AB063070.1, AL359583.1, AL117583.1, AK025209.1,AK026741.1, AK026571.1, AB060916.1, AK026784.1, AK025092.1, AL117585.1,AK027160.1, AK026950.1, AL512689.1, BC006525.1, AK025524.1, AF125948.1,AK025708.1, AL512765.1, AL442082.1, AL122118.1, AL133113.1, BC006807.1,AF057300.1, AF057299.1, AL136749.1, X72889.1, AF097996.1, BC006164.1,AL049382.1, AL137523.1, BC004265.1, AL133081.1, L30117.1, AL136915.1,BC003682.1, AB046642.1, AK027200.1, AB063071.1, AL050108.1. HMUAN45 137833072 1-2695 15-2709 BF975230, BG177292, BF683936, BF972280, AW452044,AW450817, AW571669, AW276243, AI223336, BF507478, AW953367, AI937821,AA354094, H45305, AI699989, AI624920, AA251791, D19672, AA922638,AI655588, AA928313, R74251, AA339800, H45245, BG056723, AI433894,AW080419, AI023763, AI040104, AI523987, AV681951, AI611728, AA769327,AI564716, N22276, AV761484, BG108350, BE672647, AW268067, AL513781,AI924035, AI925463, AI811192, AI613144, AL037558, AV688427, AW083111,AI963101, AA825509, AV734888, AW955613, AL135022, AW020693, AA437293,AW197174, AI910902, AI954468, AA584251, AA420722, AW963250, AI318569,C21335, AA292158, AI742728, AV692108, AI311892, BE906230, AK027899.1,BC001812.1, AB046039.1, U42766.1, AL133016.1, AF069506.1, BC007548.1,AK025761.1, BC002643.1, AB049892.1, BC008893.1, BC002697.1, BC007199.1,AL133568.1, AK026603.1, AF218004.1, BC002736.1, AF227198.1, Z48796.1,AK000205.1, BC004383.1, AL133557.1, X79204.1, BC004529.1, BC001817.1,BC008285.1, AF090900.1, AL035067.2, BC006487.1, AL353957.1, AL137281.1,AK024978.1, BC008796.1, AL136321.5, AB009690.1, AK025860.1, BC007674.1,U31501.1, BC002839.1, AB060842.1, AF094480.1, AL136781.1, S71381.1,AB060229.1, AB060927.1, AF218014.1, BC000749.1, BC001829.1, AK025798.1,AL133113.1, AJ238617.1, AF044221.1, AK026494.1. HMVBC31 138 8255981-2542 15-2556 AL513958, AL532289, AL513957, AU141081, BE740204,BG166399, BE904675, BE891108, BG256305, BE744952, BE905626, BE742828,BE899088, BE745625, AV653746, BE866918, BF982216, AW957312, AV723081,AI819405, BE281510, BB514995, BE856665, AI818085, AW612700, AW963890,BF038873, AW005883, BF111236, N31954, AI570554, AI814284, AI743921,AI373828, AW963892, BF001263, AI073849, AW978642, AA705064, BE858940,AI078328, AI831014, AW963886, AW081533, AW953584, AA150396, BE906561,W78108, AA934651, W79933, D53129, N92092, AI669184, W03272, AA594574,AA719546, AA688147, AI042436, H47299, AI304898, BG012798, R35487,AA724939, W46177, BG012794, AA661822, W46540, AA158922, AI968456,R44002, AW277188, AA352968, T75515, AW365085, BE278604, AI754560,BE817848, R94999, H60086, H59434, AI868335, N69447, F19605, AA156578,D54824, AA903411, AA449263, Z24956, AW857481, BE073224, BE466451,AW857479, AI468314, T33942, H47300, Z46090, T30256, R41822, F03578,Z40826, N36752, BG149926, R94915, AA993003, R32790, AA577458, AW594657,Z44501, AI383141, AA449397, D80727, AA365266, BF757856, AA040902,AA768178, AA768128, AI391494, AA814775, BE140388, BG035024, AI814155,AI940059, BF435821, BF435237, R34285, AW300688, AA984028, BE140425,N34605, BF448850, AW169682, AW805217, BF855415, AW751033, BE934304,AA627953, AW834022, R32791, N55681, BE172132, AW751067, AA143108,BE019916, BF759114, T19783, AW835471, AL031847.17, AF064084.1,AL117548.1. HMWBL03 139 822861 1-2582 15-2596 AL532317, AW976696,BG258766, BE784103, BE781381, BG115099, BF215477, BG163228, BE868152,BG119548, BG118210, AW978736, BE547477, AI992158, BF103579, AW394038,BE537694, AW835469, BG256663, AW070824, BE614387, BF031478, AW157294,AI743202, AI193598, BF029929, BE538143, AW303817, BE464933, AA939106,AW835466, BE869327, AW835470, BE966420, AW394036, AI831483, AW163057,AI979181, AA306435, BE613678, AA749314, AI094155, AW157089, AW362974,BF240145, BF217794, AW731659, AI878985, AW362965, BF795374, AW956998,BF217096, AA146858, BE568486, AW162479, AA648921, AW753912, AW362949,AA311937, AA908739, AI922877, AI879487, N51950, AA406456, AW362962,BE350612, AI346620, AA306611, BG055455, AA651863, AA775633, AA768709,AW614887, AA774684, AA284818, AA813993, AW362967, AW769884, AA581615,AA146857, AI378205, AW362950, AI382916, AW362951, AW403413, AA586521,AW407973, AI674283, H59390, AW362956, BF913578, BF914518, AW169393,BF914514, AI473650, BF914275, AA406348, BF916334, BF913574, AA379531,BF108888, AW610254, AI225213, AA377822, BF095168, H60046, AA372701,AA465473, BF210038, AA310305, AA360185, BE914123, AA332342, AA120901,D81998, W21240, AA331393, AI382409, R18124, BE697930, AA736861,AI351496, AW752542, AA312498, AA971457, AI223218, AA377328, AW964009,AA096093, AW673672, AA300637, BF915447, T24898, AW163350, AA248513,AW389592, N95719, N53714, AW854099, AW366952, AI690275, AA492352,AA745999, AW975618, AW960465, AV718692, AW973445, AW966534, AV718931,AW973541, C14331, AW966330, D50979, AV718489, AW964468, AW966059,D51423, AV720533, AW949645, AV699866, AW959136, AW973474, AV720791,AV719324, AW965175, AV720731, AW966398, AW973307, AV718707, AW966386,AV719557, AV720616, AW966331, AW978661, AW949654, AV724520, AW959202,D80248, D80166, AW978634, AW966369, AW973490, AW966389, AW960473,AW959799, D80188, C14389, D59859, AW975613, D59619, D80210, D51799,AV720151, AW960553, D80240, AW958992, D80253, AV719822, AV718938,AV718633, AW975605, AW966378, AA305409, AW966053, AW973488, AV720211,AV720878, AW966368, AW966029, AV699447, AW966397, AW958993, AV722801,AV723927, AW949656, AW949642, AW966399, AW966531, D81030, AW966075,AW966065, D58283, AV744690, AW973334, AW966333, AV720203, AW973447,D80212, D80366, AW966022, AV718440, AV720028, D51060, AV699550,AW965185, AW965197, AV718770, AW966013, AW973482, D80022, D80219,AW956397, AW956434, AW966041, D80043, AK027642.1, AY029179.1,AK027628.1, AL021808.1, AB028859.1, AF058696.1, AB002449.1, AF271371.1,X67155.2, D34614.1, D88547.1, D50010.1, AB038216.1. HMWCG28 140 8474131-879 15-893 AW197242, AA115972, AA283140, AI768512, AI262126, AW299591,BE501477, AI492452, AI470922, AI925912, AI479591, H99611, AW392956,N53011, H58193, BF930214, H89604, AW361279, N34132, AW865961, BF933761,BE252200, BE083984, N35841, AF061944.1, AJ296290.1, AC004765.2. HNECW49141 639117 1-475 15-489 AL162497.20. HNFCY57 142 877653 1-2833 15-2847AV741792, R94860, AW468866, AW176538, R94861, C01539, AW793380,AI954796, AI819545, AI583966, AI590630, AI147877, AI812091, AI274484,AA814517, AI783997, AI950729, AI637584, AI376425, AI866458, AW198090,AI696714, AL514455, BG001315, AL514469, AI473536, AL514015, AI364167,AI469262, BG254286, AW152621, AI885664, AI972497, BF724894, BF724284,AL513977, AI126920, AI421222, BF868489, BF752870, AI633125, AI469425,AW152182, AI279925, BF970652, BF669151, AI864102, AI701097, AI915291,AI432644, AI538564, BG179993, AI633317, BF811804, BF753014, AW088717,BF752997, AI828239, BG122005, AW105296, AI499570, AI174799, AI266643,AK027194.1, AL080163.1, AB047878.1, AF090934.1, AL389935.1, AK027173.1,AL117587.1, AL110223.1, Y14314.1, AL080139.1, BC006463.1, AK025435.1,BC008037.1, AL389947.1, AK026593.1, BC004945.1, AL122116.1, AB055331.1,Y13350.1, AK027172.1, AF124728.1, AJ299431.1, AL137533.1, BC004264.1,AK000414.1. HNFGR08 143 825417 1-1422 15-1436 AC006369.3. HNGAK51 144603910 1-901 15-915 AV731286, AW085751, BE156019, BF826830, BE067011,AI732911, BG260565, AV763498, BF747038, AV759172, BF816106, AA493475,AW405593, BE300645, AI457389, AV691908, AV696428, AV684596, AV695357,AV760383, F08248, AV730391, BF673743, BE063437, AI832009, AA583394,AW150209, AA515728, AA984258, AW575171, AV738383, H07953, BE150580,AV762783, BF681619, AA176972, BE748332, AW303196, AL035703.20,AL133445.4, AC024561.4, AC012039.10, AC010583.5, AC005844.7, AC026400.3,AC006477.3, AC022493.12, AC007000.2, AC005803.1, AC007207.22,AL138849.12, AC007097.4, AC068130.3, AL049650.8, AC006059.3, AC006334.3,AC008012.8, AC001231.2, AC009955.4, AL133409.14, AL133244.1, AC010585.6,AL121989.12, AL110502.1, AL133463.16, AC011740.7, AL513008.14,AL022147.3, AC011900.6, AC012150.16, AL109759.4, AC090527.3, AC090947.1,AC027126.4, AC004386.1, AC004814.2, AP001667.1, AL121578.1, AL157791.4,AL132639.4, AL031274.1, AL139109.14, AL499582.13, AC078841.4,AC073964.3, AC005939.1, AC022073.13, AC012170.6, AP001660.1, AC090946.1,AC002288.1, AL035604.15, Z83843.1, AB000882.1, AL049870.3, AF238375.2,AC005274.1, AL139322.13, AC008280.4, AC026172.3, AL078646.29,AC004887.2, AC019212.4, AC000029.17, AL359644.10, AL451103.7, L11910.1,AL009051.1, AP001666.1, AC002418.1, AC022443.4, AL139382.12,AL354760.11, AL158832.13, AC009194.8, AC009102.9, AL008710.1,AC005901.1, AC004859.2, AL157886.11, AC019205.4, AF205588.1, AL353764.9,AL391415.12, AC019097.5, AC004600.2, AL162551.3, AC025097.41,AF198097.1, AC016776.6, AP000122.1, AF265340.1, AL139193.4, AC010205.5,AC008784.6, AL136303.15, AC012312.8, AL360270.18, AC021752.5,AL136980.5, AP000751.4, AC012450.9, AC005409.1, AC008733.7, AC084782.2,AL096791.12, AC079127.28, AC007345.5, AC007671.7, AC009455.8,AL392048.9, AC024247.4, AC016770.10, AP000506.1, AC026310.24,AC010223.5, AL022165.1, AC021851.4, AC016748.3, AC003029.2, AC020898.5,AC007374.6, AL358612.8, AL133383.10, AC008066.4, AL359636.17,AC007637.9, AP000054.1, AC034145.5, AC004701.1, AF224669.1, AC073366.3,AP001680.1, AC004067.1, AL353692.14, AP001716.1, AC015592.6, AL359397.3,AL132774.20, AL160281.17, AC009996.7, AL157713.10, AC000113.1,AL031432.1, AL391827.18, AC025962.5, AL117337.25, AL136231.12,AP001677.1, AC004934.1, AL049589.15, AL136123.19, AC069282.6,AC009961.11, AL512307.12, AC005076.2, AC004458.1, AC016948.4,AP001727.1, AL163213.2, Z68870.1, AP001720.1, AC000120.1, AL389889.11,AC010369.6, AC010679.6, AC002128.1, AC007543.4, AL391139.19,AC090710.16, AL049830.3, AL137191.5, AL035530.11, AC011242.8,AL389888.8, AC007558.3, AL021397.1, AP003697.1, AL161415.2, AC004998.2,AC004741.1, AC007963.7, AC087857.2, AC019100.4, AL354937.12, AC068724.7,AP001671.1, AL035587.5, AL109804.41, AC073332.13, AP000350.1,AL358372.11, AP001329.3, AP001717.1, AC019206.4, AL356244.12, Z84480.1,Z93020.1, AL157955.5, AL096793.20, AC005725.1, AC025159.28, AL357507.9,AC005926.1, AC008462.6, AC022201.4, AC004478.1, AC022459.6, AL450342.14,AL590762.1, AL354861.11, AL138783.6, AC017006.4, AP002008.5,AL031963.40, AC084373.24, AC006160.9, AL031123.14, AL137787.11,AC090017.18, AP000053.1, AP000168.1, AP000121.1, AC004216.1, AL357150.7.HNGAM58 145 688114 1-1142 15-1156 AW023672, AI284640, AL138265,AW500125, AW269488, AV763540, BF677892, AW472872, AW303196, AV763558,AW301350, AI307608, BF942454, AV760133, AA630362, AW088846, BF668217,AI568678, BE047069, AA469451, AV761188, AL046409, AV761608, AI708009,AV757425, AW731867, AV761403, AW502975, AW419262, AW274349, AV740801,AW327868, AV761317, AI963720, AI821271, AV760106, AW407578, AW238278,AW193265, H71429, AV760207, AI334443, AV758994, AA491814, AV763633,BF130107, AI613280, AI350211, AA493708, AI281881, AA661948, AV759580,AV713396, AI744188, BF592311, AI151261, AI431303, AV760937, AW438643,AV762139, AW576391, AW872676, AV761498, AV759329, F36273, AW473163,AW975425, BG058664, BG222131, BG171096, AV763354, AW276817, BG231262,AW088202, BG179731, AW270270, BF813686, BE672637, AA665330, AI754336,AU118745, AV757607, AI357551, AV728928, AL138455, BG249643, AV762015,BF942059, BF942223, AI345654, AI061334, BE154617, AL119691, AV759204,C06339, AL048925, AW276827, AW029038, AI254316, BE139146, AA579063,AI079389, AL047427, AW662543, AW406162, BF592200, AA623002, BE677379,AA074130, BG059568, BF337291, AI085719, AW575165, AI610159, AU147193,AI635818, AI814735, AI471481, AL040130, AW103758, BF965007, AI718446,AF330238, AV760614, AV762050, AV728425, BE350475, AA601876, BE018774,AW615709, BF841869, AI537506, AV725627, AV763255, BF475381, BF793766,AV760817, BG104686, AW021583, AW960468, AW576503, AI580652, AW265009,AV759239, AV658688, AU147800, AA581903, BE677158, AI289067, AV764307,AV760395, AW872575, AW339568, AV761631, AV764398, BG236735, AW969698,AA468131, AW969694, AW406755, AI828463, AV764530, AV763971, BG056088,AV759382, AV761786, AW474299, AV762959, BF851403, AI148277, AI791150,BF942311, AI565581, AI283911, AW574794, AF074677, AI340453, AI376100,AI570261, BG177715, AW410400, AV728410, AV761294, AV709707, AI446601,AV760774, AI471543, AI921649, BF680805, AI358571, AV764035, BE072475,AV710066, AI679782, AI281697, AI537955, AI270117, AW972879, AV762098,AI696962, AL041690, BF030810, AI355206, BE208673, AW833862, AI654588,AU145314, AW162049, AI341664, BF840676, AI929531, AV749274, F28204,AV731764, BG032943, AW504669, AA604362, AV725423, AI754658, AI076766,AI796627, AI375710, AV761941, AA610491, AV764659, AI921061, BE349302,AI873916, AI571512, AI358812, AL049757.14, AC005288.1, AL354872.9,AF109907.1, AL162272.10, AC000003.1, AP001753.1, AC005318.1, AC015540.9,AC087071.2, AC008736.6, AC068799.14, AL022316.2, U18391.1, AF348209.1,AC007537.3, AL138837.12, AC009470.4, AC004452.1, AF181896.1,AL034405.16, AC004787.1, AL161655.8, U57006.1, AC006337.4, AL353625.5,U18392.1, AL139346.6, U18396.1, AP001699.1, AC002470.17, AL445528.16,AL445123.11, AL031279.1, M37551.1, AL133419.15, AF077058.1, Z69917.1,Z82198.2, U67221.1, U67211.1, AC005730.1, AL117329.8, AL121891.22,AL445222.9, X54176.1, Z98048.1, AC004922.2, AP001594.1, AC008812.7,AL358334.3, AP001717.1, AC003101.1, X74558.1, AP000009.2, D83989.1,AP000228.1, AC004695.1, X75335.1, AL359091.10, AB012286.1, U18390.1,AC005180.2, AP000140.1, Z93241.11, AC055740.17, AF015148.1, AC009137.6,AL121934.17, AF015160.1, AP001695.1, AF121897.2, AL163218.2, AJ009611.6,AC009267.15, AL137011.9, AP000088.1, AC007308.13, AL133376.6,AC010320.9, AC010596.7, AC020754.4, AC010332.7, AB060228.1, AL096701.14,AC018639.8, AL355497.14, AC016642.5, AC025463.5, AC002545.1, AC007225.2,U38673.1, AC007878.2, AP003352.2, AL353596.13, U57004.1, AL121785.48,AC008755.6, X53550.1, AC004622.1, AF015156.1, AC006157.2, AL445686.14,AC022211.5, AC006132.1, AL355358.9, AL355580.13, AC007038.3, AC004477.1,Z83001.1, AL031311.1, AF015151.1, AP001694.1, AC004652.1, AC000360.35,AL139022.4, AC008447.7, U57009.1, Z84482.1, AF317635.1, Z82245.1,AC007298.17, AC083875.1, AL354774.17, AC020915.6, AC020750.3,AL353628.7, AC007014.1, AP001132.4, X55932.1, AC026733.4, AP001838.4,U18395.1, AC006509.15, AL138878.10, AL031655.8, AJ010598.1, AC009196.13,AC005522.2, D87675.1, AL022721.1, AE006463.1, U57007.1, AL391137.11,AL139317.5, AL049761.11, AC008169.2, AL390785.15, AB056411.1,AL137077.31, AC002115.1, AL023881.24, AC005161.1, AC022392.4,AL049539.21, AL353734.12, AC005077.5, AP002906.2, AC090514.1, X55924.1,X55925.1, AF131215.1, AC005019.1, AC010601.5, AF235093.1, AC009247.12,U18394.1, U57005.1, AL132825.35, U38672.1, AC080011.21, AL133328.13,AC008440.8, AC002542.1, AC016903.3, AC010654.8, AP001672.1, AL158830.17,AC003051.1, AF015153.1, AL138958.18, AC008039.1, AC008403.6, AL352984.4,X55926.1, AC010642.5, AL160163.24, AC010650.8, AP000141.1, AP000049.1,U18393.1, AL133396.2, AC005324.1, Z83826.12, AL157369.7, AL139101.13,AC011448.3, Z83841.1, AC009227.3, AL136231.12, AL132875.22, U18398.1,AL365509.8, AC011548.4, AC004890.2, AC026787.4, AC005553.1, AL353594.13,AC068713.8, AC008775.6, Z68332.1, AL162385.16, AC009303.3, AJ277546.2,AL354857.13, AE006639.1, AL353759.8, AL109925.11, AL136311.7,AP000851.4, AL391839.9, AC005821.1, AL162503.12, AL031176.8, U18399.1,X54180.1, AL590426.6, AC003682.1, AC004919.1, AL590240.5, AC005370.1,AC005018.2, AL135797.10, AC040160.4, AC005670.1, U57008.1, AC005527.3,AC009626.8, AL590763.1, AL163032.3, AL031735.9, AC006948.4, AL513527.9,AC008536.6, X76070.1, AL136365.9, X55930.1, AC019183.3, AL035458.35.HNGFR54 148 695748 1-481 15-495 AC007316.4. HNGGA68 149 638116 1-57115-585 AB052201.1, AJ236595.1. HNGHZ69 150 899289 1-1181 15-1195AC011239.5. HNGKT41 151 836061 1-1034 15-1048 AW862214, AW859811,AW862215. HNGNO53 153 836063 1-811 15-825 R37935. HNHFE71 155 8344871-889 15-903 AV718844, AV720464, AV700229, AV743601, AV722801, AV701043,AV701431, AV719000, AV701017, AV737584, AV701248, AV701012, AV745724,AV745723, AV740535, AV701332, AV742667, AV718681, AV699447, AV745080,AV701118, AV741012, AV743654, AV701166, AV742720, AV718858, AV723927,AV744934, AV701163, AV701261, AV720731, AV742001, AV743008, AV738934,AV701154, AV720607, AV719568, AV745488, D51250, AV746385, AV699927,AV745392, AV724520, AV744773, D80043, AV744771, AV701121, D80253,AV745831, AV720220, D59787, AV746335, AV701335, AV701125, D80219,AV746162, AV745369, AV701149, AV701443, D80227, AV721784, D59275,AV701428, AV700622, AW973447, AL038531, AL037726, AL039629, AL039625,AL039648, AL038837, AL039074, AL039678, AL039108, AL039538, AL039564,AL039156, AV700889, AL039109, AL039659, AL039566, AL039509, AV744768,AV719783, AV720034, AL045794, AL040992, AV746102, T24119, AV718016,AL039924, AV699479, AV758878, T24112, AL039128, AL044407, AL036973,AL045337, AL037051, AL045353, AL039386, AL039423, AL038821, BF294063,AV718692, AL045341, AL042909, AL039410, D80240, AL043422, AV718002,AL038025, AV717989, AV717980, AV701782, AV718018, AV717988, AV731085,AL036725, AL044530, AV745917, AL039150, AL043445, AV717983, AV744770,AV745366, AV741888, AV717984, D80210, AV718489, AV735727, AL043441,D51423, H00069, D80045, AV717959, AV745350, AW064110, AW013814, D80134,AV717972, AI535983, AV717956, AV717963, AV717962, D59619, AV717990,BE439760, D80391, BF508972, AV717966, AV718023, D80193, AW976625,AV717960, AV717970, T23947, AV717941, AW949642, AV718010, AL043423,D80196, AV720812, D80168, AJ293456, AV717965, AV718020, C14227,AL037639, AV701357, D80949, AW975312, AL039085, AW969383, AV717958,AL036196, AV717949, AW969322, R47228, AW451070, D59927, T02921,AV717955, AV745490, AV717948, AV699669, AV717971, AL037615, AV718001,AV717946, AV718021, AV717978, AV701227, AV745583, AV718006, D80366,AV718008, AW965158, AV717968, AV718017, AV717964, AV720203, AW949643,AL037526, AV718013, AV717952, AV718014, AW452756, AV701055, AV701004,AV717967, AV717976, AV742995, AL036767, T11051, AI535783, AV717961,AV701145, AV745920, AV717943, D81026, AV717942, AL036117, D50995,AW063533, AV718707, AV723097, AV719822, C14014, AV717985, AV717993,C75259, AV745621, AV717974, AW949645, AL036238, AW975203, AV719913,AL037601, AV717973, AC074089.8, AF271371.1, D34614.1, X73004.1,AJ244004.1, AJ244003.1, Z96142.1, AJ244005.1, Y11923.1, Y11926.1,L27636.1, AC007269.2, AC066580.3, AC024910.4, AL023553.5, AL157373.23,AP001827.4, AL356115.9, AL080239.11, AC012614.6, AL008627.1,AL049641.10, AC010608.6, AC005225.2, AC010127.12, AP002768.3,AC004919.1, AC005332.1, AL031123.14, AC002451.1, AL136226.9, AL021451.1,AL022396.1, Y18000.1, AL133377.10, AL390739.8, AC017091.8, AC027288.26,AC005079.6, AC005694.3, AC005527.3, AC006007.1, AC005529.7, AL049792.11,AC019106.3, AC022428.6, AC016591.6, AC078962.30, AC004534.1, AC007198.6,AC006320.4, AP000227.1, AL136975.6, AC004595.1, AC034198.6, AP000087.1,AC006975.2, AP001694.1, D42052.1, AC073348.8. HNHGK22 156 597451 1-89515-909 AC073193.10, AC008269.4. HNHKS19 157 778392 1-776 15-790AW237081, BF222713, AI954694, BF057788, AW590509, AW136373, AA833546,AW139260, D80045, AW949645, AW964468, AV718844, AW949642, D80212,AW966389, AW949656, AW949631, AW949643, AW949618, AV720211, AV744012,AW966531, AW975618, D81030, AW973334, AW966013, AV742048, D59619,D80210, D80240, AV744690, D80022, AW964488, AW966053, D59502, D80166,D80219, D58283, D59927, AW975621, C14331, AW949655, AW966029, D80043,AV723927, AV718440, AV720028, AW959628, AW965177, AW965163, AW978634,AW966534, AW973541, AV699550, AW960553, D80195, AW966041, D80391,AV719822, AW966054, AV718692, AW966050, AW958992, AV738340, AV719324,AV719783, D51423, AW949653, AV718800, AW978661, D51799, AW966065,D80253, AV720464, AV718770, AV718489, AV720203, AV719188, AW973307,D80227, AW966062, AV724520, AW959597, AW959570, AW973485, AV719557,AV720731, AV720791, AW964756, AV699447, D80193, AV722801, AV718633,AW949641, AW960465, AW975605, AV699927, AW965184, AW959202, AW960564,D80269, D80196, D59859, AW966022, D80188, AV699746, AW959799, AW962245,C14389, D80164, AW964737, AW973482, AW978648, D59787, AW962082,AW949632, AW965197, D59275, C15076, AV700229, C14429, AV718938,AW949654, AV718707, D57483, AV718931, D80038, AW958993, AV723097,AW959136, AW959062, AW964477, AW956434, AA305409, D59889, AV742732,AV719468, AV699669, D80366, AW949646, AW949658, AW973474, AV719049,AW966075, AW965158, AW949629, D59467, AW949633, AW965185, AW949657,AW366296, D59610, AW965196, AW973447, AW966043, D50979, D50995,AV720812, AV721386, AW973488, AW956397, AW960473, AW965175, D80378,D80024, AW973330, AW959582, AI905856, AW959469, AV700889, AV720878,AW975613, D80241, AV718530, AV741220, AW973465, C14014, AW960504,AW753053, T03269, AW960454, AW178893, AW966023, AW960532, AW966059,AW949630, AW966030, AW975623, C75259, AV720654, AW960474, AW960570,AW752082, D51060, AV701004, AW966397, AV742001, AV742667, AV701125,AV701335, AV701166, AV701043, AV701332, AV701017, AV701248, AV701431,AV742430, AW965176, AW375405, AV719913, D80248, AV701149, AW179328,AW178775, AW966032, AV701419, AV701415, AV701154, AV719628, D80268,AV700159, AV720150, D51022, AW966332, AV701443, AV702035, AV699479,AW964766, AV701422, AW966560, AV699866, AV701130, AW951169, AW964532,AV719727, D81026, D80949, AW966368, AV720533, AW177440, D51250, D80168,D80134, AL136170.12, X67155.2, AF271371.1, D34614.1, AF058696.1,AB028859.1, D88547.1, AB002449.1, D50010.1, AB038216.1. HNHKV56 158800877 1-1639 15-1653 H86448, AC009396.5. HOACG07 159 792928 1-128415-1298 AL529455, AL527447, AL519665, AL530298, AL526667, AL520518,BF312602, AL527270, AL523402, AL525526, AL525575, AL532418, BE795641,BF689773, BF690313, AL532417, BE793892, AL523401, BE798089, AW961032,BF978883, BE794106, BG117486, AL517000, AW375519, AW375527, AI761506,BF836264, BF237461, AA738047, AU123303, AI744657, AI573291, AA058761,BE259536, AI765107, BE502073, BF087384, BE888732, BE779165, BE394031,AW246799, AA700013, AW631125, BE786533, AA759011, BF315852, BE515115,H38495, BE889852, AI375009, BE702984, AI587531, AI148268, AL516999,AI809308, AW250662, T15960, AI890594, AI298775, BF102631, AA838498,AW137267, AI798469, AA838214, AI825338, AI200417, AU149319, R00301,AI085034, AI436070, AA036978, AI040364, AI537302, AA587887, AI341279,T99954, AA588536, AI368583, BG171023, AA366003, BE536848, AA573353,AI357177, AI474992, BG178921, AW872754, AI248063, AW337164, AW082916,AW663937, AW589264, AA830722, AA719102, T85297, AA683570, AW473394,AW630338, AI927184, AI500302, H78131, AI991231, BE644792, BF055078,AI766544, AI365563, T32118, AI344370, AI469218, AI370730, AI668957,AA036979, BF591154, AW973504, T85508, AW404558, AA365119, AI739608,AI263592, T98466, BG231108, AW663122, AA338808, AW167738, T98407,BE788568, F31030, H27770, AA434441, AW103958, AI364615, AI347419,AV756067, BF436680, BF436679, AK000557.1, AK022713.1, AK024220.1,AL109804.41. HODBB70 160 520196 1-590 15-604 AW079904, AW207285, H18498,R37566, BF852425, BF102683, AC006322.2. HOEBK60 161 789396 1-220415-2218 AL515934, AL520231, BE618778, BE618245, BE782129, BF056891,BG121474, BG250670, BG168174, BE905489, AI633878, BE042542, AL518067,AW515316, AW088411, BE536123, BE218306, BE644805, AW207435, BF087512,BF570490, AI818209, AI752319, AW962355, AL536159, AI669659, AA902264,AW105148, AW410334, AW083012, BF515266, BE465947, AL518068, AI927938,BG260989, AI420205, BE465917, AA043792, AI743602, AI283114, D81907,AL515935, BE546476, AA186486, AI417561, AU131122, N66098, AA573278,AA431514, AI752320, H14424, R59054, AI819645, AI631297, W00707,AI434568, BE221654, BF104164, AA973972, R59803, AA350599, H11851,AA724174, R17805, BF924661, H19130, AI638738, AI440413, N98699,AI702887, AA431188, AA280575, BF838288, R61472, AA653570, R77568,AI753861, C00128, BF998349, H29435, BF377857, AA348799, R18745,AI962149, AA809488, D78858, AA305344, AA360504, BF837084, BF352331,AI440138, AL135399, AA300827, AA329088, H83314, AW089455, D62361,AW811797, BE889780, BE561984, AI925346, BF374906, D78824, AW796219,AW811796, BG027920, N55732, BG036911, AW796258, AW410333, N90043,Z25249, R61473, BE899608, AA043666, AA174177, AA350598, BF089446,AW514435, AA095955, BF089445, BE736007, AA092014, AA096434, AW275782,AW275777, AA427677, AI624981, AI749472, AA704575, BE171096, AL044986,AW089135, W19853, BE940131, BF514239, BE163882, BE163878, BF243117,AK023143.1, BC004183.1, BC007219.1, BC000935.2, AK001928.1. HOFNB74 162762821 1-1022 15-1036 AL528391, AV705461, BE742621, AW957840, AW957916,AA313780, AA469996, BF699406, BE897665, AA206557, N31702, AA459482,BE790325, BE899574, AW971024, AA460494, AI052029, AI761638, H55824,AA628498, AA412069, AI027538, AW514954, AI884599, AI419408, AW469200,AI992152, AA024623, AA581877, R62921, AI142045, AI275439, AI066572,AI939991, AA328484, AW002064, AA025955, W73635, W52125, AA492218,AL513597, AL514791, AL514935, AV723772, AV682289, AA954252, AW080838,AW166645, AV681668, AI906328, AI149592, AV682266, AL514087, AI907070,AI815383, AI220734, AV723204, BG108147, AL515047, AL514473, AL119049,AI624859, AV758217, AV756703, AV681857, AL515373, AV758592, AV758738,AL514627, AV682441, BE619513, AV723062, AV693157, AV733397, AL514543,AV705644, BF724691, AV682351, AV710479, AL513803, AV706777, AV661310,AV708119, AA328485, AV682479, AV730922, AV755581, AV681630, AV682252,AV682772, AI345860, BF673434, AI590482, BE777769, AV682051, AV758110,AV757205, AV682330, AL523243, AV682099, AA022458, BG058208, AL536633,AV682335, AI682106, AW132121, AV756477, AI907061, AL516344, AV729334,AL514359, AL524807, AV682466, AV711509, AV682385, AI525064, AV682521,BG108324, AL514075, AV682496, AV734638, AI349772, BG105099, AV734425,AV681586, AV681951, BF732407, AV733470, BF037607, BG109857, AV729701,BG259801, AV711355, AL513985, AL513907, BF940608, AV682249, BF725868,AL513763, AI345111, AI344182, AV661309, BE881155, BF795712, AV682809,AV681858, AV733824, AL513817, BF054789, AV711924, AV681872, AV682645,AV757096, AW168591, BF982085, AV755207, BE966443, BF107577, BE208710,BF348329, AL047042, AI569870, AV681949, BF726322, AV682222, AW071349,AW467961, AV734318, AI524991, BF791874, AV723953, AL514803, AW827203,AL513631, AV682476, AV758806, BE891101, AL519188, BG109125, AV704350,BF968041, AL513719, AL514657, AL514085, BF916588, AV734180, AV729890,AV655645, AV695052, AI207510, BF036115, AL514691, BE613622, BF337043,AL515041, BG120135, BE048026, BF339420, AI868831, AL514823, BG257535,AI349645, BG259943, AV724569, AA528822, BG179633, BF981774, BG109969,BE047863, BE966577, AV693410, AV732941, BE878186, AV704928, AI909662,AL513693, BF340104, BG033403, AV755614, AL121270, BG179993, BG254754,AI340582, AL512733.1, S78214.1, AL133640.1, AF090934.1, AL442072.1,BC008387.1, AL389978.1, AL050393.1, AB048953.1, AL049938.1, AF090900.1,BC007021.1, AB056809.1, AF078844.1, AB055303.1, AF090943.1, AL136586.1,AF125949.1, AL050146.1, AL157431.1, AL117457.1, AL133016.1, BC008417.1,AL442082.1, AL110196.1, BC008365.1, AL122050.1, AL137527.1, AL353594.13,AL117460.1, AL136787.1, AB056420.1, AL133606.1, AF090903.1, AF090901.1,AB050510.1, AF104032.1, AJ242859.1, AL133258.16, AK026608.1, AF218014.1,AK000212.1, BC008488.1, AB049758.1, AL080060.1, AL390167.1, AL359596.1,AL359601.1, AL049452.1, BC003687.1, AL110221.1, AL136749.1, AF106862.1,AC006336.4, AB063046.1, AL136789.1, AF111847.1, BC003683.1, AB047615.1,AL096744.1, AK027868.1, AL162006.1, AB060887.1, AF090896.1, AK026865.1,AB048964.1, AL050149.1, AL136892.1, Y16645.1, AB063070.1, U42766.1,AK026741.1, AB019565.1, AL050116.1, AB055361.1, AL122093.1, AB060916.1,AC005940.3, AK025339.1, AK025084.1, AL050108.1, AL499604.9, AL121952.18,AB060908.1, AC010879.2, AL445236.22, AB056768.1, AB063008.1, AL049430.1,AF091512.1, AL162083.1, BC001967.1, AL133075.1, AC005225.2, AK026045.1,AK025958.1, AL049314.1, AC026787.4, AC007375.6, AL049776.3, AL133344.28,AB048974.1, AB047801.1, AL049466.1, AL034374.2, AC026464.6, AL035067.2,AL136799.1, AC006357.5, AC007172.6, AF219137.1, AL353802.14, AL050277.1,AC007298.17, BC006807.1, AC006435.7, AL133557.1, AL080137.1,AC026307.16, AC004686.1, AC005886.2, AF097996.1, AL360294.11,AC010077.1, AC020558.4, AL080124.1, AC007043.3, AL137283.1, AC000111.1,AK026855.1, AK027096.1, AC002464.1, U95739.1, AC009145.4, AL389982.1,AC006039.2, AC024247.4, AK026744.1, AL122123.1, AL133093.1, AL133080.1,AL136844.1, AC005000.2, AL133565.1, AC004690.1, AL137459.1, AL035587.5,AL136768.1, AC006371.2, AL512746.1, AC021325.5, AP001699.1, AC020921.5,AK000618.1, AC005291.1, AL122121.1, BC002733.1. HOSDO75 163 862049 1-88815-902 AI375670, AI990134, AA732220, AI494146, AA172039, BE777959,AA258154, AI394315, BF086933, AA172291, BE093382, AA456756, N57268,BF086946, AU138426, AU139896, BE093384, AA113041, AA258916, AK002100.1.HOSEI81 164 562778 1-883 15-897 AA418350, AA418237. HOUDE92 165 5808661-1270 15-1284 BE736091, BF237553, BE781264, BF686547, BE313480,BE872070, BF313936, AI138711, AI348027, BE502126, BE258631, AA524244,AW873570, AI982983, AI367855, AI052179, N90758, AA325647, AW419076,AW873111, AW008195, AI304671, AI367495, AW964887, AI609692, AA019213,AI279349, AI581275, AI224904, AI141287, H14110, H41440, AI017367,H29060, H29163, AA482386, AI471043, AI742262, AI262559, H52568,AA872715, R60248, H06091, AI041676, BE856821, H86160, H86771, AI241156,AA872384, R60761, AW131262, T31006, H56455, H95225, AA535480, AA678522,AA953998, R93546, R47352, BF968234, C04826, N39943, AA779062, T31180,H69216, AA017105, AA738315, AA019233, C04344, C05015, H17526, R99865,H84704, AW025505, AA057567, N72695, H86419, W02476, N27200, AA001522,AW194286, AI264419, AI220672, AI290418, T30927, AI620442, AA985424,R49316, H86772, AA725465, R91429, R93547, AA017106, AI074855, H95701,H69217, H95226, AW188581, AI678424, AA057566, AA326095, AA976949,H56456, W57713, AW166317, Z42112, AA775239, AI864069, AA918031, H85105,AA015626, AA977988, AA429622, R99866, H14085, AI000910, AI431360,Z38375, W57838, AA015625, R57558, AI949351, AI262422, AC005865.1,AF217967.1, AK027366.1, AC005912.1. HOVBD85 166 827362 1-1115 15-1129AC009039.6, AP001721.1, AF015262.2, AJ229043.1, AC008015.5. HPCAB41 167758003 1-2573 15-2587 AW130635, AA732548, R66294, H02322, AA992616,R63528, AA089513, R80947, BG180648, AL110237.1, AL157372.18, AL022394.3.HPEAD23 168 773409 1-568 15-582 BG037089, BF973374, BG025260, BF981319,AI827721, AI220233, BE876017, AA910948, AW663886, AA728767, AI279770,BF727458, AA972390, AI051448, AA932444, AI346841, AA740783, AI186713,AA948231, AA905780, AA918553, AA884145, AI268749, AI346070, AA858123,AA857640, BE275406, AW025402, AI262503, T95182, AL389983.1, AK025239.1,U90913.1, AF234997.1, AF028823.2, U78525.1, AL137298.1, AL389943.1,AK025254.1. HPFCI36 169 855966 1-865 15-879 AL516624, AW967335,AI346493, BF969871, AI379068, AW813968, AI435632, AW439597, AA160513,AA111896, AI129000, AI803023, AI587653, AI247913, AW080897, AA111878,BF197837, T58186, H04232, W07286, BE243262, BG165835, AA046003,AW028757, BE882257, BE393612, AA357180, AA085677, AA085834, AA621577,R36594, BF733978, AI014838, AL536330, AV753531, AV751871, R36593,AV752854, AW605869, AA341976, T58072, AW955926, AA576671, BF825158,BF245058, AL527071, AI367586, N79788, AA321931, AI566375, AI709192,AW379008, AA441898, AK000452.1. HPFDI37 170 862056 1-338 15-352 H55085,AA434130, R25258, R20029, H14658, AW950901, BE275081, R19886, BE727676,BG248105, BF345809, BE730221, BE904350, AC000090.2, AF106697.1,BC007489.1, AF171054.1, AF044212.1, AF166126.1, AF166127.1, AB019694.1,AB019695.1, AF201385.1. HPIAA80 171 829972 1-905 15-919 BE865466,BG170320, AW043782, AW662099, AI933030, BF432372, AI553724, AA629903,AW341957, AW073315, AW972918, AA542856, AA380138, H22229, BF667499,C02428, BF573889, BF695553, BF697671, BF982558, BE694971, BE961006,BE865295, BF507508, AW467509, BF571682, AW372886, H25153, AA302738.HPMFH77 173 702014 1-1877 15-1891 BF969970, BG253932, BE857961,AI185063, AA985520, H97907, N70065, AA503843, N68939, W94388, AA829801,AA349438, W00572, AI301208, AA349459, R23765, BF813707, R23718,AI129242, H97073, H47246, AI382737, BF818365, AW027760, AW027780,W74636, AI471120, AL042488, BF932339, BF891282, AI401774, BE859019,AA775471, AI685740, AL356095.11, AC007270.2, AL139100.9, AL078600.15.HPRBH85 175 695752 1-1659 15-1673 AI147467, BG252600, BF354490,BF354491, BE999965, BF032961, W52563, AW512426, AI810178, BE274472,AI188557, BF432115, N25987, AI700626, N29859, AI659619, N29340,AI031999, AA974460, AI267374, BF593262, N36618, AL538054, AI350777,AI656701, AV724003, W01296, AI949788, Z39752, H09136, AA234945, W60255,AA635309, Z43693, H09192, AI583723, BE830918, N67638, AA371469,AA706920, AI537632, AW028490, AI799012, AA234944, R34999, T64063,AA855109, BF082755, BF332778, BF082768, BF082759, BF082766, BF328302,N57281, AW301576, AA610602, BE181224, BE830920, R49386, BE009565,BF332781, T63991, N83625, AA495939, H26811, AI348901, AI564500,AL039274, AW051088, AI866469, R41605, AL514691, BF871314, BG029058,AI889180, AW834282, AI433611, AW089844, AA806757, AL118781, AI370623,AI471429, AL039086, AI619525, AI628325, AA464646, AW076124, BE875959,AI345688, AI583558, AL121365, BF033757, AL048351, AI285439, AI638644,AI621341, AI524654, AL046466, AI474646, BF970162, AW195253, AW020381,AA808175, AV704934, AV750565, AI445069, AI619820, AI537677, AI874107,AI309306, AI927233, AI891084, AI589428, AI472487, AI270183, AL079963,BG169738, AW083572, AA806719, AI859464, AI951123, AI634457, BF812960,AA470491, BE906646, AI475371, N92140, AW827107, BF811808, BF750886,AI684127, AA654216, AI972070, AI473536, AV734747, AV733582, AI590755,AW150557, AI499963, AI932503, AW192300, BE393784, BF971340, AW050850,AL046595, AA825826, AI582932, AI923989, BE909549, AI978703, BG250575,BF525577, AI536685, AA857847, BG253684, BE892118, AV701597, BG170663,AW080140, AV682112, AW025279, BG260760, AW021091, BF796402, AI923559,BG260287, AI610446, N25033, AI702527, BE966968, BG256090, BF970123,AI861973, AW088183, AI564212, BG034586, AA693331, BG034746, AL138376,AW023072, BF089679, AV726156, AW105087, AI866090, AI479292, AV682403,AW021256, AI932794, AV757018, BG255493, AW076127, BF527697, AA838435,AI560873, AI590043, AI440260, AV747571, AV656932, AI433590, AW029566,AI819976, AW020710, AI609331, AV762892, AI225000, AI357599, BF680133,AI954721, BG260524, AI815232, BF724651, BE877142, AL045950, BG026483,AW019988, AI566613, BF892007, AI524179, AI368691, BF766531, AW075382,AI567971, AW080076, AV682366, AI539260, BE047852, AW172745, BE439677,AW089275, AW020419, AI079736, AL039390, AI879377, BE536417, AI500061,AI306610, AW168875, AI537516, BE621256, AI799313, AI096771, T69241,BG250789, AV682250, AI225004, AI698391, BG113851, BF680131, AI741158,AK027690.1, AB050514.1, AL162002.1, BC008899.1, AK026959.1, AF155656.1,AF326206.1, AF265236.1, BC001967.1, AL137459.1, AK024747.1, BC006287.1,AF006516.1, AF117959.1, BC001236.1, BC002373.1, AK025113.1, AF245044.1,BC001964.1, BC003590.1, AL136882.1, AL389935.1, AL137480.1, AK026389.1,BC002733.1, AB048881.1, BC008946.1, X61970.1, AK027096.1, AL359583.1,X99226.1, AB051158.1, BC008708.1, BC009395.1, BC004925.1, AL137711.1,AF274348.1, AF274347.1, AK026534.1, AK024588.1, AL512733.1, X59812.1,AK025015.1, BC001199.1, AL136864.1, AB062978.1, M92439.1, AL137523.1,AL359615.1, AL137550.1, Y10080.1, AL110196.1, AB044547.1, AK027142.1,BC002476.1, AJ006417.1, AB055370.1, AF195092.1, AK026647.1, AF026816.2,BC009026.1, AF353396.1, AL136622.1, AK025906.1, AK026541.1, AF131821.1,AF044323.1, BC000778.1, BC003658.1, AL137657.1, BC008488.1, AK025209.1,Z37987.1, AL122100.1, BC005843.1, AK026434.1, AL117435.1, BC001328.1,BC000090.1, AL136586.1, X72889.1, BC003637.1, AK027129.1, AF056191.1,BC003122.1, AK026649.1, AK000647.1, BC004945.1, AB055361.1, AL049464.1,AK026626.1, AB060852.1, BC005854.1, AF205861.1, BC001670.1, AK026506.1,BC006807.1, AL133637.1, AK026633.1, BC008920.1, BC007364.1, BC000386.1,BC000643.1, AL080146.1, AL137478.1, BC008836.1, AL359596.1, AK025084.1,M85165.1, AK025092.1, AL512746.1, BC007767.1, S77771.1, AL136893.1,AL353940.1, BC001844.1, BC000235.1, AL050138.1, BC009398.1, X83544.1,BC000316.1, AL137267.1, AL137557.1, AL133080.1, AB060837.1, AL133049.1,BC000761.1, BC008673.1, AK026518.1, AK027146.1, AK026613.1, BC002466.1,S76508.1, AF227198.1, AJ406930.1, BC001082.1, BC005002.1, BC000751.1,AK027081.1, AK027116.1, AK024594.1, AK026057.1, AK027210.1, AL117587.1,BC001785.1, BC005168.1, AB056421.1, AL133062.1, BC002985.1, U73682.1,AY033593.1, BC006181.1, AL049283.1, AC009364.8, AK026462.1, AL137258.1,BC007375.1, AL389939.1, BC000007.1, AF111112.1, AL137627.1, AL512704.1,AK027152.1, AL136615.1, AL049382.1, BC006440.1, AK027173.1, Z82022.1,BC002343.1, BC006494.1, BC006345.1, AL137663.1, AF106697.1, BC007556.1,AL512718.1, AB060839.1, AK000250.1, AK000197.1, BC007420.1, AL050143.1,AL096720.1, AL157433.1, AJ406932.1, BC003410.1, AF285836.1, BC004297.1,AL137275.1, AL110280.1, AC002467.1, AC020908.6, AK026600.1, BC002491.1,AB060893.1, BC007255.1, AF114784.1, BC007852.1, AB048995.1, BC004874.1,AB052200.1, BC008078.1, BC001675.1, AK027136.1, BC005890.1, AF057300.1,AF057299.1, AL356103.8, BC007674.1, AL080124.1, AL133104.1, BC005858.1,AK024533.1, AK027137.1, AL122104.1, BC002541.1, AB050410.1, BC004951.1,BC007204.1, AL050172.1, BC007456.1, BC006196.1, AF183393.1, AK027164.1,BC002495.1, AK025632.1, AB050431.1, AB060888.1, AF061795.1, AF151685.1,AK000618.1, U42766.1, AL136787.1, AK000653.1, AF102166.1, X66417.1,BC000077.1, AB060229.1, BC004960.1, X82434.1, AL049339.1, Y14040.1,BC004991.1, AF159141.1, BC006091.1, BC008591.1, BC003591.1, BC002519.1.HPRCD35 176 853551 1-695 15-709 AI952238, BF966633, BE673553, AW249944,AW673164, AI491912, AI433456, AW027835, AI434093, AA040338, BG152387,AI744101, BF589019, AI433927, AW388710, BE710661, AW027844, BF951319,AW514110, BE893648, AW235679, BF951645, AA853738, N77918, BF904963,AW027796, BF951640, AI820008, BF802330, BF802123, BE091385, AA040337,D20818, BG116710, W07085, BE348578, BF979894, BF448283, AI806099,AA746652, AI269951, AI370493, BE251472, BG255671, BE743054, BE873348,AA034242, AI269933, AI494531, AA193194, R01841, AW130830, R71213,BE746974, BG252660, R01109, AV746580, AV709278, AA910706, BF204537,R94047, N62862, BF832992, AI828509, BE700205, AW899366, BF951647,AA323326, AL042486, AL527593, T97110, AW176293, AA886453, AA319188,AI521632, AV699431, BF922964, AV700764, AV700026, W26006, N93989,BF951643, AA193234, N87415, BF825093, BF841081, BE695594, BE695488,AV695783, AV692484, T69241, AA398143, AV682403, AV682366, BE907663,BG030601, BF978949, BF965959, AI801106, AL039456, AI499161, AI635132,AL359611.1, AK025633.1, AB037802.1, AK027681.1, BC002349.1, AK026408.1,AL133088.1, AL359583.1, Y10183.1, AB048881.1, AC011450.4. HPTRM02 177812879 1-1746 15-1760 AL524458, BE738365, BE797125, BE799999, BG029222,BE745922, BE545163, BE907437, BE799866, BF305271, BE544399, BF663830,BE796881, BF308083, BG169861, BE350925, AW385462, BF307517, BE797270,BE743037, BF668016, BG180312, BF974123, BE737908, BF663981, AW247807,BE513095, BE906969, AL138083, BE255971, BF664455, BF338518, BF244474,AL536412, BG231717, BG121312, AW005562, AI357069, BF000625, AA644049,AL523557, AW513359, AA632166, AW246260, BF892728, AA706163, AL520864,BE746537, AW245080, AI879390, AA496904, BG177219, AW005067, AW276591,BE791039, AW804483, AA738041, BE747177, BF869837, BE251828, BE875024,AI088680, BE297879, BF948818, AA831030, BE559592, BE561590, BF340321,AW248071, AA860150, AA149920, T63138, AL524459, AW439742, AI609027,AW804577, AI659057, AW886264, AA193529, AA057835, BE743405, R73214,AW194065, BE562027, AW075497, R75945, BE559810, AA706533, BF894712,AI468114, AW249614, AA335528, BE795304, AA827797, AI302055, BF129302,AI750232, AA427422, BF930249, BE560497, AA860105, BF939406, AA335848,AW404930, AW571830, R76783, T15952, BE560176, BG152613, BE267829,AW991408, BE269966, AW991532, BF664249, AL138082, BE269643, AW575878,BE797429, AW071243, AA304216, BE791865, AW945716, AW875302, R37100,AA682206, BE277420, AA193433, AW751797, AA352416, AA587756, AI818900,AW518507, BE939890, AA852530, R07062, BE900192, BE296328, AA931598,BE671371, T32042, AI033227, AA353903, R82530, BG121259, AI281709,BE389644, H28650, AA534672, AA548317, BE866982, AW084505, R73151,AA349275, T62995, BF205162, AI219302, BF688975, BG117867, BE748125,BF128654, AW772768, R82480, AA665591, BF434544, AW246149, BE859039,AA687496, AW403743, AI738846, BF893795, BF772867, BE388333, AW874200,BE890138, BE791538, BG027900, BF129181, AI468932, C00531, AW150444,AW338439, BE388322, BF931213, AW875234, AW385458, AW991401, AW875290,AW373139, AW385460, AW581536, AW875235, AW875239, AA687440, AI948428,BE727787, AW403641, AW393066, AW875349, AW581529, AW875238, AW875305,AW875255, BE748665, AW875292, AW875249, BE383820, AW875301, AW581521,AW581531, AW875245, AW875307, AW875248, AW875296, AW875241, AW875360,AW581537, AW875368, AA653357, AW385464, AA852531, AI878829, AI079775,BF874873, BF991409, AW403272, BF772016, BF688505, BF592857, AW518551,AW991487, BG012697, AW835133, AW875362, AW962437, AA078519, AW581533,AF218020.1, AF151364.1, AF077353.1, AK027367.1, AF197060.1, AF250287.1.HRADA42 178 827302 1-1121 15-1135 BG167431, AI870419, BF794745,BF212001, AI379833, AA894530, AI339336, AI336165, AW173013, BF688231,BE546835, AW615315, BG029651, AI660120, BE793058, AI961630, BG024470,AI418065, AA946777, AI697018, AW629846, BE538634, BF694672, AA126483,AW957695, AA948109, BE565388, AA864307, AI281293, AI124079, W58372,AI372055, AA918864, AI284979, AA961355, BF245466, AW627534, AI018252,AI804228, AA115687, AI123356, AA460235, AA938579, AA806449, BF667170,AI191797, BF218360, BF211069, BF666624, AI201697, BE789077, AW958886,BE888833, BE566320, BF678487, AA181956, AI280166, BF701292, AA187579,AI476152, AA975500, AI262806, AA633371, T86966, BF027457, AA670154,BE858489, N54918, AI285113, AI282777, AA928294, BF184831, AA856633,AA554905, AA952898, AA939258, BF245493, BE565724, H01916, H04478,BF029426, AA358260, AA283086, AI498851, AA070685, BF209151, BE252410,W04639, AA503091, D20722, AI473325, N78134, BF207942, AA553782,BF477790, BE302428, AA383311, BE568842, W31735, AI718566, BF695644,T56012, BF239325, N21275, BF696213, BE897499, AA651925, H78232,AA383310, AI583297, BF694034, AA296522, R70784, N40501, AA282901,T31842, BF081525, R70837, BF665566, BF668121, AI381360, BF243257,AW630758, R80104, W58050, BF700860, BF593090, AA358261, BE394694,C14037, BF822945, BF211844, BF699997, AA329615, AA463798, BF239695,N31210, AA375691, AA932915, AW188939, AA770225, AA381668, AA969062,AI284357, BE379498, AW754363, AA918735, BF902310, AV683902, AV695726,AV691171, AI863382, AA911767, AI270183, AW983832, AI590423, BF814449,AI491842, AI932818, BF909758, AI886123, AV713022, BG166654, AI679550,AI690813, AL036631, AI591420, BF885000, AI802542, BE783206, BG260287,BF337479, BF816037, AW190891, BE621256, AI680498, AL041772, AV689304,AL036403, AV729462, BG029053, BE011880, BF814516, AW827119, AI817552,AI344817, AI345745, BG110517, BF726207, BF061283, BG026714, BE964614,BE877142, BG151388, AI950877, BE964820, AV733679, BG026746, AV734259,AV757000, AW827106, BE906123, AI872910, BF339322, AI923989, AI888621,AL135022, AL039086, AI699011, AW020095, AI608936, AI559296, BG112718,BG112239, BF856052, AI370890, AI538764, AI611738, BE048071, AW827211,AA640779, AI589668, BF338002, AW268083, AL036274, AW834302, AV712229,AV651983, AI927755, AL079963, AW157767, BF340889, BF969228, AL040205,BF904189, BF924882, AL040241, AA738104, BG256592, AV705384, AI336575,BF814357, AI284517, BF814360, AW269097, AW827102, BG121335, AW191003,AC011890.4, BC001013.1, AB034206.1, AL110115.38, AK024538.1, AF218014.1,AK026741.1, BC006412.1, AK027164.1, AK024588.1, AL512746.1, AL512718.1,AK027116.1, AL133560.1, AF028823.2, AL049430.1, AL137521.1, AL162002.1,AF252872.1, AK026592.1, AB052200.1, Z37987.1, BC007021.1, AB051158.1,AF091084.1, AB049758.1, U42766.1, AL050024.1, AL049465.1, AK026506.1,AL136893.1, AB060839.1, AL137533.1, AK000486.1, AL049466.1, AB060929.1,AB047801.1, BC009212.1, AB055368.1, AF106862.1, AK024545.1, AL137557.1,AL512689.1, AK025254.1, AB060916.1, AK000391.1, S78214.1, AL137488.1,AL133606.1, AL389935.1, AK027868.1, AL080124.1, AL133104.1, AK025857.1,AK024992.1, AK026086.1, AK000445.1, BC006164.1, AB060908.1, AB055366.1,AL050116.1, AF217991.1, AL133113.1, AK025484.1, X72889.1, AL080074.1,BC008280.1, X65873.1, AL136882.1, BC006195.1, AF227198.1, AL137294.1,AL050277.1, BC001418.2, AL133093.1, AK026597.1, AJ242859.1, AL133075.1,AF111847.1, AL157482.1, BC006508.1, AL137523.1, BC006440.1, AK025349.1,AK025798.1, AK025573.1, AL117457.1, X53587.1, AL512719.1, BC008387.1,BC008382.1, Y16645.1, BC004958.1, AK026452.1, AL359615.1, AK025708.1,AL050092.1, AK026855.1, AK025967.1, Y10936.1, AF132676.1, AL512754.1,AK026045.1, AF061836.1, AK026797.1, AL389939.1, AB063046.1, AL117416.1,BC008417.1, AK025524.1, AK026927.1, AL359618.1, BC006807.1, AL122093.1,BC008893.1, AK024524.1, AL136786.1, BC004530.1, AB055370.1, AK026626.1,AL137459.1, BC007355.1, AK025092.1, AL133568.1, U78525.1, AK026600.1,AL136805.1, AL137479.1, AB062750.1, AL136799.1, AL080086.1, BC007389.1,AL512750.1, AL137526.1, AK026647.1, BC008070.1, AK026642.1, AL122123.1,AL049382.1, AF183393.1, BC000316.1, AB060825.1, AB060852.1, AL162062.1,AF090900.1, AK026608.1, AL389982.1, AL122121.1, AF104032.1, AL137539.1,BC007326.1, AK026480.1, AL390154.1, AL137560.1, AL137271.1, AL359583.1,AK025414.1, BC001963.1, AL117460.1, AL080158.1, AL023657.1, AL512765.1,BC002733.1, AL137292.1, BC008365.1, AB055361.1, AK026534.1, AK027114.1,AL122049.1, AF353396.1, AL136622.1, AL049283.1, AF069506.1, AK026164.1,BC004951.1, U58996.2, AF210052.1, AK026784.1, AL096744.1, AL133077.1,AL353956.1, AL117435.1, AK025465.1, AF057300.1, AF057299.1, BC003687.1,AK024594.1, BC002457.1, BC009403.1, AB047615.1, AB052191.1, AL353957.1,AB047941.1, AL117583.1, AB048954.1, AK027213.1, AL137538.1, AL133557.1,AK000421.1, AL110221.1, AF090903.1, AK025312.1, AL080137.1, AL137527.1,AF056191.1, AL136787.1, U88966.1, AF078844.1, AK026528.1, BC003602.1,BC002643.1, AK025906.1, BC004370.1, AF225424.1, BC005168.1, AL122106.1,BC004362.1, AL050172.1, AL133098.1, BC006180.1, AK000647.1, AL137550.1,AK025435.1, AL136792.1, AL133016.1, AL137658.1, BC004556.1, AL136864.1,AL136586.1, AL359620.1, AB063100.1, AL080148.1, AL136540.1, AL136784.1,AK000718.1, AL137463.1, AB019565.1, BC009284.1, AK026464.1, AL136928.1,X82434.1, BC009033.1, AB060826.1, AL389978.1, AL050155.1, BC008899.1,AL162003.1, BC009395.1, AK000137.1, AB047897.1. HRADF49 179 8664811-2690 15-2704 AL521382, AL518826, AL521381, AL530977, AU124017,AL040407, BE791530, BF981293, BG254592, AU118953, BF344355, BE740053,BF303862, BF569193, BF689517, BG169396, BE746952, BE299333, BF343050,AL040965, AI890747, BE262124, BE262749, AW952814, AL039282, AW084007,AI911096, BF337955, AU158472, BG253868, BF690437, AW270132, AU145398,AA531346, BF725565, AI803664, AL039531, AW663883, BF980374, AA284526,AV704289, AA464099, AV727566, AA725631, AA287069, BE313910, AI937483,AA459615, AI362056, AW269445, AA994395, AI827109, AI963554, AA531242,BF725564, AU145598, AV751889, BE047669, BE302399, AA292966, BG033996,AA417174, BF036819, AI159963, AA575850, AL044057, AI309235, AW268808,AA417070, AW581576, H93876, D53731, AA703065, H17707, BG004754,AA598746, BF878254, AI751892, AI863325, AA699411, H93516, AA612854,AA326192, AA608913, H50994, H06488, R77015, AW802244, H17796, Z21667,D60336, H06546, D53158, AI499464, H17089, H03185, H51646, BF843440,R70504, AI751893, AW104937, D60587, T15778, AA463962, AI698963,BF570178, BE093116, AA367859, AW073342, R74223, R70596, BE903088,AA339790, AI611402, AA827345, AI872839, AV747217, BF207394, T85774,F17581, F22580, AA333977, H03985, BF886534, AA459390, AA781915,BE041929, AW178545, T91167, AA074564, BE075634, T07088, AW273719,BE378883, AL529296, BE835059, R67434, AL518827, BF216264, AI609819,AW749542, BF830925, BE621938, BF834744, AL040408, AW387038, BF888401,AA868869, AI287476, AI445862, AA742390, AA766077, AI955866, BG164250,BC001206.1, BC001098.1, AK025822.1, AK021732.1, AK027448.1, AF308473.1,BC000860.1, BC005888.1, AK026615.1, AK000618.1, BC009360.1, AB049629.1,BC008742.1, AF249267.3, BC004265.1, AB048974.1, AB060929.1, AK000445.1,AK026894.1, AL133081.1, AK000027.1, BC007034.1, BC002415.1, AL161953.1,AF078844.1, AF114784.1, BC007556.1. HRADN25 180 800628 1-1211 15-1225BF970417, BE871509, BF794109, AL526454, BE613934, BE905773, BF530960,AI911227, BG177658, BF034925, BG108075, BF203211, BG180755, BF691907,BF344447, BE781907, BE387776, AW149618, BE395988, BE262824, BE379253,BF978384, AW025001, AI760168, AW082806, BE391375, BF130003, BE139640,BE544410, BE909917, BE388549, BE884607, BE614181, AW339993, AI752742,BG230765, AI700463, AI926722, AA843550, AI936652, BF665754, BF698346,BE884217, BG056573, AI095901, AI554935, AI138745, AW593083, AW958242,BE622189, BF571310, AI693589, AW469544, BF883936, AI357218, AI277497,AA972697, AI199598, AI241950, AW452978, AI830389, AI024270, AA401585,BF886169, AA936697, AA931135, AA401345, H64785, BF923986, AI206725,AA873221, BE222978, BF948219, AA084391, AA988399, AA987748, AA838228,AI752743, H50235, AI275531, AI362439, AW450568, AI362511, BF842031,AA618048, BG024996, BE908231, BE937874, H06750, BF841745, H15722,H06700, AA937768, AI879499, BE763002, N50809, BF817866, AI366339,H64022, H15344, H20386, R09749, H18813, H30571, AW363996, AI363966,AW083589, AW449564, AA663409, T91307, AA025560, Z44943, BF341574,H20195, BF868861, AA991841, AA970173, Z40694, T84887, AA345553,AA378558, AI963935, AA081540, AA725384, R09748, BE966128, AI243967,AA025704, R23438, BE561045, BE392574, H40825, BF214147, AA885941,BG009780, W96140, BF695813, W92486, H41770, H50269, BF928386, AA018786,AA580941, AF289485.1, AB055802.1. HRDDQ39 181 840405 1-762 15-776AA564252, AV763026, AV763058, AI499954, AI654738, BF763954, AI066646,AW813668, AI537020, AI801505, AI491765, AI251576, AW502796, AW272294,AA935409, AI040051, AI306232, AA503298, BE062545, AA225406, AI583466,AW274191, AI755202, BF771774, AW962251, AI635028, AV764259, AC008073.4,AC020604.9, U95740.1, AB020867.1, AF001552.1, AL049712.12, AC025168.7,AL512347.14, AC012469.9, AC007066.4, AC002996.1, AP003439.2,AL357752.19, AC073273.9, AC008372.6, AP001883.5, AC004973.1, AC013264.4,AL163285.2, AC073657.5, AC009516.19, AC012284.5, AL031230.1, AC005034.1,AC012476.8, AP002815.3, AC011485.6, AL365338.17, AL160397.17,AL008635.1, AL158830.17, AL033518.14, AC007172.6, AL391065.6,AC005768.17, AC007425.16, AL031123.14, AC005911.6, AC090947.1,AL157838.24, AL591398.2, AC009756.9, AC009274.9, AC006600.4, AC007748.2,AF312915.1, Z99716.4, AC008733.7, Z83822.1, AC004675.1, AL121753.30,AL121754.18, AL109804.41, AC006511.5, AC005157.1, AL133324.13,AC006480.3, AL080243.21, AF088219.1, AC004887.2, AL139353.3, AC002563.1,AC006435.7, AC005081.3, AL160236.4, AC005859.1, AC010651.7, AC022414.6,AC025679.4, AP001752.1, AL442167.1, AC018738.4, AL031685.18, AL352978.6,AC025262.27, AP000557.2, AC012320.6, AL133229.40, AL031311.1,AC008440.8, AC003962.1, AL034372.33, AL133295.16, Z93020.1, AC004209.1,AL078581.11, AC010654.8, AC007226.3, AL356503.18, AP001922.4,AC010789.9, AC018690.5, AF168787.1, AL080314.29, AC011510.7, AE000658.1,AL160492.5, AL133244.1, AL117380.28, AL161629.10, AC010320.9,AC002546.1, AP000692.1, AC011742.3, AC008720.6, AC005023.1, AC025588.1,AC004584.1, AC004848.1, AP001725.1, AF019413.1, AC005013.1, AC011443.6,AL121899.37, AC006449.19, AP001694.1, AL359682.4, AL109825.23,AC034240.4, AP000355.1, AC011473.4, AC008569.6, AC009570.13, AC007381.3,AL365295.4, U91321.1, AC007363.3, AC009502.4, AL157882.5, AC006130.1,AL445201.14, AL137061.12, AL135818.3, AD000092.1, AL121578.1,AL035404.20, AP000513.1, AC069548.4, U91323.1, AC008507.8, AC005747.1,AC005071.2, AC009503.3, AL121653.2, AL359644.10, AL031622.1, AL031659.9,AC004526.1, AC010102.3, AC006270.1, AC021752.5, AC068319.4, AF031078.1,AP003357.2, AC008511.6, AC078846.2, AL445184.11, AC009275.6, AC009194.8,AF030876.1, AC018663.3, Z84474.1, AC008556.5, AC002350.1, AC010543.8,AC003108.1, AC007276.3, AJ003147.1, AC008764.7, AC015982.9, AL049830.3,AF003529.1, AL080239.11, AC020931.5, AC004125.1, AL391827.18,AC010150.3, AC005043.2, AL137222.17, AC011005.7, AC020750.3, AC004859.2,AP000356.1, AF001549.1, Z94801.1, AC005914.1, AL133342.14, AC007308.13,AL355836.3, AC009953.4, AC005138.1, AC008493.4, AC006116.1, AP001052.1,AL122001.32, AL139100.9, AP001732.1, AC009137.6, AL035450.1, AC003037.1,AC006042.2, Z84484.1, AC004089.25, AL357519.19, AC002312.1, AC026368.37,AL449223.7, AL359695.6, AL022159.1, AC009955.4, AF279660.2, AC008616.6,AL139230.25, AC005952.1, AC006443.1, AL121586.31, AC008551.5,AL035367.5, AL133245.2, AL354720.14, AC005740.1, AC023114.5, AC007318.4,AC090951.1, AC066597.4, AC003049.1, AC008821.5, AL162571.9, AC019171.4,AL136162.17, AC022083.6. HRDER22 182 688056 1-529 15-543 BF727044,AI748813, AI694426, AU148346, AI860331, AW206751, H19708, AI368623,BF685348, BF061078, C15772, AW973165, F22520, F29231, F36814, H67240,AA550873, AI871877, AI003318, AA883557, H81558, H20045, AA609021,AI679361, BF683664, AI216706, AW079340, D61490, AI867271, C01198,BF946359, AI215944, F18487, AA970129, BC003585.1, AK001252.2. HRDEX93183 816046 1-1667 15-1681 AL527900, AL529036, AL529408, AL533906,AL533907, AL529035, AL527941, BE903615, BE791071, BG166982, BE299248,BE793113, BE909498, BF205960, BE900230, BF663336, BE900477, AU138677,BF317122, BE902376, BG105338, AL046917, BG248168, BE387420, AU128036,BF796169, BF674884, BE734698, AW247351, AW245938, BG122744, BF794696,AI832791, AU139448, BE295651, AI310124, AW674400, AI792211, AW515975,BE265061, AW245495, AW675728, BE394504, AA226400, AA569956, BE300693,AW388658, AU150370, AI890679, AW402628, AL527942, AI962952, AI221330,AI245352, AI601125, AW469172, BF957886, W80352, AW188512, AW405360,AI215909, AI564190, AI208267, AA533187, AA633700, N95345, AA431700,AA311285, AA643585, AI865794, BF221803, W26197, BF241479, N90770,AA040058, BE251149, AW512882, AA031577, N30739, AI890616, AA349670,AA994951, AI372503, N59649, H91459, AW731826, AW672782, BE265966,BF807476, AA554209, BF802350, AA226371, AA737167, AW592984, BF802840,AA349671, H72140, AW006451, AA176708, AA037422, BF807473, AI352253,AA972235, AW934951, AI905350, AU158023, T95955, AI733502, AA229521,AA226888, T95961, AA226924, AA323327, BF767741, BF371957, W67484,BE767129, AW247493, T95866, T95860, AL046918, AI148858, AA876362,AA216424, AA936123, BF240778, BF476991, H13591, AA813410, AA173027,C03952, AA641404, N78203, AA865022, AA876167, AI879823, AW518440,BE303017, AI015568, H26512, AI784024, AA040044, W25254, AA431493,AA031456, AI275659, AW513500, AA861578, H54187, N35164, BE770665,R77485, AW088915, AA384005, AA470650, H13222, BF767990, BE241964,R38117, AA368017, W80351, AA336001, BE872227, AA054613, H91107,BE546333, AA054553, BE171388, AI378983, R69693, R38031, W21999,AW749739, AI364635, AI961834, BE242695, AA303798, R57459, AA994783,AW958926, AB026628.1, AB018357.1, BC002773.1, AK001420.1. HRDFK37 184840381 1-714 15-728 BG107419, AA210943, W77904, AA729879, N27422,BE833271, BE833267, BE698411, BE698282, AA116105, W72144, AA460896,AA460724, D19856, AA116106, BF911568, T74524, AA664126, BF830998,AA658018, BF747320, AA568853, BG015078, N66744, BF346026, BE090515,H85032, AW902135, AW902110, H86546, AA059247, AI627868, C16358,AA017169, BE090514, AI224184, W38349, AU147414, BF800607, AA016279,AA507035, AL035413.19, AL033529.25, AC011449.6, AL359091.10, AC020913.6,AC008379.6, U91321.1, AL354720.14, AC023510.16, AL357559.16, AC002404.1,AL445222.9, AC011895.4, AL034422.24, AC007620.30, AC004867.5,AL391839.9, AL359092.14, AC004983.2, AL031427.15, AC003029.2,AL132775.29, AC007193.1, AP001711.1, AL034429.1, AL136526.27,AC020904.6, Z93015.9, AC004686.1, AL079342.17, AC008946.6, AC022383.3,AC008755.6, AC008687.4, AC005972.1, AL034548.25, AC009123.6,AL390241.19, AC000379.1, AC021325.5, AC006312.8, AL137139.9, AC073138.3,AL138720.19, AP001753.1, AL512430.14, AL118520.26, AC005516.1,AL355336.15, AC006480.3, AC005800.1, AC005921.3, AC004622.1, AC008551.5,AC010271.6, AC024082.6, AF196779.1, AC002312.1, AP000997.1, AL035249.6,AL590762.1, AC005081.3, AL359813.23, AL121656.2, AC005015.2, AC010092.4,AC009812.17, AL136441.16, AC012170.6, AL022311.5, AC022384.4,AC008171.3, AF283320.1, AL021154.1, AC005071.2, AP000424.3, AC008397.7,AC020928.6, AC008132.35, AC007151.2, AL121983.13, AJ277546.2,AF129756.1, AL121897.32, AC004963.2, AC005670.1, AC005585.1, AC083871.2,AC011811.42, AL109804.41, AC087071.2, AC008491.6, AL591398.2,AC005098.2, AC007384.3, AP000030.1, AL391136.9, AC005887.3, AC005952.1,AC002430.1, AC018809.4, AC011462.4, AC027125.4, AL121890.34, AL137802.7,AC018828.3, AC008403.6, AC006111.3, AC004125.1, AC018663.3, AC025588.1,AC005089.2, AC008543.7, AC004820.2, AC009131.6, AC034207.4, AC019227.4,AC022007.3, AC004216.1, AC005326.1, Z95114.19, AC021999.4, AC005519.3,AC004966.2, AL390298.13, AC020983.7, AC010543.8, AC034193.4, AC008155.9,AC005529.7, AL355312.24, AL135978.4, AL034346.31, AL023553.5,AC007664.12, AC006120.1, AC020728.4, AL049766.14, AC007066.4,AC005736.1, AC011718.2, AC011484.4, AC069285.8, AC002350.1, AC011455.6,AC018808.4, U07562.1, AC009362.8, AC008569.6, AL022165.1, AC020754.4,AC004087.1, AL121834.20, AC005488.2, AC020716.3, AL136137.15,AL136303.15, AC006946.20, AP002812.3, AC005914.1, AC090954.1,AC026776.4, AP000514.1, AE006463.1, U52111.2, AP001169.1, AC009247.12,AL031311.1, AC004644.1, AC083867.4, AC009137.6, AC002310.1, AL031228.1,AC018500.3, AC002565.1, AL133312.3, AC004821.3, AL022336.1, AL138688.27,AC005184.1, AL023807.6, AC002470.17, AL049636.22, AL021453.1. HRTAP63185 780698 1-2562 15-2576 AL530903, BF980210, AV713636, AV714538,BF795697, BG165908, BG034785, AW954212, AA476834, AA454040, BE787658,W87846, W95796, AV723163, AA210879, BG121323, AI140750, AA394298,BE544064, BF110177, BG260733, AW957532, AW835225, AV715167, AW043868,W95753, BE675523, AI830085, AV684273, BF669098, AW575257, AI719282,AW402599, AA594596, BF030937, AV751996, AA151651, BF439829, AI972457,AA203350, AW835231, AV698320, AW835223, BF195333, BF245739, AI458367,BF217997, AW103450, AV646999, AA443779, AI804705, AA779750, AA609993,AV646707, AI161426, AA883267, AV761220, AW105020, AI859827, N21490,AA769659, AI961457, AI963269, AV748401, AV702852, AA454948, BF477944,BE378300, BF507584, AA398140, AA829928, AA723665, AA152423, AI066682,C05924, AI342144, AI818909, AI949342, AW173168, H95180, AI150177,AI744274, AI373130, AI936317, BF131934, AW935736, AI373127, BF184877,AW848815, AI168246, AW630390, AA703773, AI809600, AI858227, AI620702,BF211545, AA453622, AW511827, BE550555, BF352641, AI811412, BF216016,AI149376, BF028661, AA777078, AA988774, AA825373, AA745603, AA447847,AI634257, AI148253, BE568959, AW474847, H50762, AW340117, AI148595,AA152318, AA455325, H18773, AA446817, AI983483, N70494, AI950667,AI367305, AA447696, AA165032, BF349702, AA595127, W37577, AI865137,W60533, H27027, AI088311, AA781728, BE244882, AA411860, AI380799,BF130302, AI927370, AA150348, AW876985, R96314, AV726405, AA729374,W32295, AA448492, AI453093, AW769995, W04863, AI263830, AA083837,AA133757, AV734814, H24217, BE564563, N99875, N77905, AA679441,AI352336, AI188487, AI432136, AA033645, AI266690, AI433965, AA877077,AA055324, W44808, H49413, AA411995, AA833544, AI300087, BE972332,AV682350, AA992809, AA814064, AA741027, AV702746, W32538, AA683291,AA621431, AA902136, AA214623, AV647110, AA663647, AA494354, BE245415,AW151578, AW150662, W60562, AA705000, AI950580, N27003, AA345942,H85708, AA133758, AI627657, AA224004, W37452, T80362, AA452695,AI146286, H49227, AW074691, BG142207, H47030, F25806, H85509, BE244420,C17218, H24204, AA480190, AV651579, AI272131, T80478, AI381311, W87586,W37696, H18682, H24218, AV647065, N29206, N28458, AW468405, BF081529,W44802, AA927134, AW821055, BF854323, AA083939, F35729, AA682763,R31829, AA148436, AA125918, H95144, BE246322, W44717, AW194993,AA729762, H50669, AA343940, BE244987, AA115539, R26021, N35260, H46491,AI902181, AI149536, R37220, AA325890, AF151885.1, AK025730.1,BC000836.1, AF135161.1, AB062991.1, AC007298.17, AF172940.1, AC022149.3,R26823, R38842, H88357, H88417, H88357, N40125, W05840, W25309, W32702,AA027857, AA027923, AA034476, AA115050, AA151732. HSAVA08 186 5808701-1047 15-1061 AA523633, BE562634, AI828787, AC008738.6, AC005722.1,AC020908.6, AC090942.1, AL035685.21, AL049843.18, AC027124.4,AC005089.2, AC084865.2, AC002465.1, AC034251.5, AC022211.5, AL050335.32,AC009123.6, AC005320.1, AC002365.1, U91323.1, AJ251973.1, Z95115.1,AL359792.3, AL133545.10, AC011444.5, Z95152.1, AC002378.1, AL139352.16,AL122035.6, AC006160.9, AL109825.23, AC005015.2, AL162430.15,AL033526.24, AP000697.1, AC005328.1, AC007907.2, AL353653.19,AC010463.6, AC007637.9, AL161779.32, AC008755.6, AC018644.6, AC002996.1,AP001712.1, AC005756.1, AC010363.6, AC005225.2, AC002544.1, AC002470.17,AC003684.1, AC011480.3, AC007277.2, AC010878.4, AC011491.5, AL022394.3,AC068799.14, AL137918.4, AP001726.1, AC006130.1, AL138827.16,AC073864.28, AL034420.16. HSAVW42 187 637660 1-581 15-595 AI336192,AI911235, BE644656, AI459354, BF030919, AI333569, AA652155, AW974708,AI700779, AA932386, AI922689, AI888953, AA848053, AI863382, AI932794,AI554821, AI539687, AW081231, AI587156, AW189415, AI610362, AA225339,AI934011, AI498067, AW168373, BG031338, AI280732, AI590423, AI590686,BF724894, BG036614, AV709522, AI242251, AV756150, AI890907, AI687065,AV682074, AI583065, AI472536, BF811793, BF812960, AW167222, AI636588,AI249946, BF970652, AW169234, AI431909, AI610115, BF981148, AI635016,AI874243, BF970768, BF727034, AI798351, AI580254, AI627988, AL037582,AL037602, AW022682, AI916419, AI872804, AW072719, AW151714, AI613038,AI470293, AV704962, AI588892, BF725644, BE965169, AV757161, AA470491,AW172723, AI281867, AL514791, AW983783, AI802542, AV682875, BG256090,AA502794, AI758437, AI609409, AI798456, AI345551, AI628833, AI590830,AI560683, AW198090, BG108070, AV733470, AI591407, AW090071, AI335426,AI348777, AI521244, AW983832, AI955906, AI288050, BE963244, AW084117,BE546262, BE783819, AL514627, AI274541, AI274745, AW059713, AI612913,AI493576, BG165979, BF726207, AW268302, BF033757, BG001235, AW104196,AI538764, AW983754, AI633125, BF726237, R36271, AL042628, AI539771,BG108268, BF528717, BF970263, BE621472, AI680498, AI269696, AV714710,AI655841, AA910956, AI890223, AI921281, AW169039, AI686073, AI583085,AV682224, AW162189, AW105601, AV648430, AV714100, AI567612, AI697372,AI702073, AW827227, BG179993, AI866082, BE018334, BG114304, AI633000,BG112239, AI950664, AL039086, AL046849, AI816947, AW302954, AV734180,AL036980, AV682791, AW169604, AI249877, AW082088, AL041105, AI866770,AI887772, AA427700, AI376180, AW002174, AW089179, BG036846, BE966927,AA807352, AI241923, AW167918, AV755589, AI864836, BE892503, AI621362,AL048323, AL040827, AI570807, AI634345, AL048340, BE785868, AI608932,BE910373, AI537677, AI879064, AW081255, AI738854, AI956080, AL080046,AI440263, AI862135, AI690748, AI865906, BG180295, BF868489, AA833760,BG108309, AI537261, BF342157, BF764528, AI866083, AI623941, AI922315,AI433157, AI870192, AI597731, AA641818, AW198112, AI637584, AI440239,AI345677, AW151729, BF753013, BF924882, AW004886, AW079336, AW983691,BF762612, AI520785, AL119863, BF344691, AW022699, BF814357, AI580694,AI923989, AI499986, BF343568, AW169848, AI627893, AI572717, AV715462,AW301513, AW081298, AA572758, BG109590, AW089310, AI554344, BF752999,BF968017, AW079859, AV656595, BF925729, BG252914, AW301505, AI620093,AW088538, AI538850, AW163834, AL036403, AL389939.1, BC005678.1,AB062942.1, BC008485.1, AK000432.1, AF000145.1, AB047904.1, AL359618.1,AK024538.1, AL133067.1, AL049452.1, AK025798.1, AL389982.1, AK025857.1,AL136844.1, AK027213.1, AB050410.1, AL137476.1, AL122110.1, AL137550.1,AK027182.1, AF090901.1, AK026057.1, AL137648.1, AL137488.1, BC008893.1,AL049382.1, AL512733.1, AB048974.1, AL136747.1, U38847.1, AF230496.1,AF183393.1, AF090900.1, BC006525.1, AL137533.1, AK026532.1, AK025092.1,AF159615.1, S78214.1, S61953.1, AK000614.1, AK026480.1, AL117578.1,AL023657.1, AF061943.1, X72889.1, AL389935.1, AJ299431.1, AF143723.1,U58996.2, AL133557.1, AF056191.1, AF081197.1, AL122123.1, Y16645.1,AK000083.1, AF057300.1, AF057299.1, AL162083.1, AL122049.1, AL137526.1,AB063070.1, AL080159.1, AL137560.1, BC006103.1, AL117460.1, AL080074.1,AK027160.1, AK026592.1, AK000418.1, AF090943.1, AL359583.1, AF217987.1,AB056420.1, AJ242859.1, AL136749.1, AL110171.1, BC008382.1, AL137640.1,Y10936.1, AL137271.1, BC008075.1, AK027204.1, AF113222.1, BC004958.1,AL359601.1, AL583915.1, AL133606.1, AK026593.1, AL050366.1, AK000718.1,AF162270.1, AF026816.2, AK026642.1, Y10080.1, AK026784.1, AB055368.1,AL117435.1, BC008780.1, AF217966.1, BC006440.1, AB047801.1, AL137529.1,BC007680.1, AK027614.1, AK000486.1, AL080148.1, AK026600.1, AL136805.1,X98834.1, AB049892.1, AL080086.1, BC008488.1, BC003627.1, AK000618.1,AL122050.1, BC009310.1, AL110197.1, AB060908.1, AL136789.1, AF090903.1,AL157482.1, AL512765.1, AK000450.1, AL137273.1, AL136845.1, AL133113.1,AL137292.1, AK027116.1, AF285167.1, AB019565.1, AL512719.1, AL359941.1,AK026533.1, BC009026.1, AL136622.1, AL136615.1, AK026045.1, AF225424.1,AL122106.1, AB056421.1, AK025084.1, AK025209.1, AK026741.1, AK027144.1,AK025708.1, AL442072.1, AL117440.1, AL122093.1, AB062978.1, AL137294.1,AK026542.1, AF061573.2, AK025383.1, AL162004.1, AK026534.1, AL162002.1,AB060912.1, AF090934.1, AL512718.1, AB048964.1, AB050418.1, AL512761.1,BC004951.1, AF210052.1, AB048954.1, AK026630.1, AB063084.1, AL133665.1,AL133075.1, AL049465.1, AF061795.1, AF151685.1, AK025254.1, BC007198.1,AL157431.1, AL137527.1, BC003122.1, AY033593.1, AL136882.1, AF207829.1,AF081195.1, X53587.1, AL137276.1, AF271350.1, BC006164.1, U39656.1,AB063008.1, AB050534.1, BC005890.1, AL353957.1, AF177336.1, AK026885.1,L30117.1, AB060903.1, AB060825.1, AB056809.1, AF262032.1, AL359620.1,AK026551.1, AL050393.1, BC007021.1, S76508.1, BC008983.1, BC008387.1,AK027114.1, L19437.2, AK026504.1, BC008070.1, AK025967.1, AK026528.1,BC008284.1, AL136786.1, AL117585.1, U68233.1, AL110221.1, AL162062.1,AL050116.1, AL096744.1, AL133077.1, AL110225.1, BC006807.1, AL050138.1,AJ006417.1, AF106862.1, AL136790.1, BC009341.1, AK026408.1, AL137429.1,BC009033.1, M64349.1, AF097996.1, AL389978.1, Z82022.1, BC006180.1,AB060929.1, AL136843.1, AL133016.1, BC003684.1, AF125948.1, AF090896.1,AB056768.1, AB060214.1, AL117432.1, AL110222.1, AL137521.1, AL137300.1,AL080060.1. HSAYC41 188 688057 1-200 15-214 AF001545, AA548754,AA909788, AW468262, AI751080, AI251827, AA576709, AI800743, AA875953,AW131183, AW149412, AW339554, AI263391, AW168132, BE300485, AI638563,AI920829, AI751079, AV700614, AI682030, BF688845, AA665727, BC008593.1,AC000159.6, AB007864.1. HSDZM54 189 637870 1-540 15-554 AV729255,AI535959, AV726938, AV701879, AV729339, AV654282, AV725709, AV705433,AV702947, AV691890, AV662257, AV705443, AV706584, AV725529, AV728243,AI557222, AV726503, AV709039, AV692176, AV758197, BF942332, BG222560,BG222322, AV738071, AA469321, BE880733, AV717185, BE881230, BE879882,BE875275, BE876183, AI064816, BE877078, AA467922, AV724819, BE877083,BE877146, AL047841, AV653804, AV707611, AA468250, AA467983, AA467864,BE874475, AA657843, AA467872, BG223149, BG231240, AV727472, BE878467,AA533928, AV756682, BF942071, AV759063, AW128905, AV759547, AV721822,AI535873, AV757055, AV715748, BE878136, BE878027, BE878818, BE873792,AV721050, AI207666, AI065052, AV762317, AV742528, AV759381, BE876648,BE877183, BE875306, AI207671, AV742491, BE876813, AV722499, BG230797,BE874917, AA468002, BE874492, AI557473, AA467862, AA468434, AW277108,AA468184, AA467920, AA467928, AI374100, AA467967, AA468143, AA468361,AI114862, AW070665, AA468920, BF680264, C16929, BE714703, AV695014,AI720411, AA468467, AW243938, AV705090, AA468095, BE896904, AV754426,AI065071, C17062, AW265193, AA094361, BG223154, AA652499, AA468996,AW129315, AI698669, BE153318, AI951338, AA654934, C17215, AA468176,BG231144, AA602107, BG231135, AA729610, AA226446, C17433, AA541818,AA550877, AI033651, AI799863, AA541815, C18736, AA467968, AA574306,AI022799, AA508188, BF942136, AA513120, AA535933, AI460289, AV745072,AV653812, AA781850, BE044950, AI287963, C18396, AA652954, AI926958,AI796602, AA978151, AW872525, AA420618, AA569429, AI749178, AI581768,AI735781, AI718674, AI418640, AA468004, BG231064, AJ202491, AA579481,AV711061, AI634214, AA480424, AA978149, AI092988, AA564192, AA658047,AV712864, BE879318, AA494138, BE168579, AA934542, AA724186, AA550867,AA468511, AW235024, AA535848, AA533509, AA527093, AA613771, AA513599,AA247586, AV729805, AW237889, AA548217, AA724187, AI735751, AA938056,AA658218, AI626072, AI749551, AA230233, AA548923, AW440526, BG231142,AA978154, AI708944, AA641087, AI707532, AV744874, BE879020, AA664671,AA654470, AA527020, AA558381, AA468395, AA494234, AA468981, AA641600,AA468310, BE174413, AA658970, AA687521, AI880361, AA484530, AI031693,AA742862, AA551840, AI749568, AI078862, AA652909, AA938041, AA664938,AA516238, AW235484, BG230835, AA657450, AV739800, AA513215, AI832319,C17475, AA572851, AA477483, AI535874, AI581596, AA508180, AA788847,AA588245, AA094820, AW265092, BE878632, AI081273, AW264966, AW265056,AV701496, AA854696, AI719891, AF004342.1, X62996.1, AB055387.1,D38112.1, AF346998.1, AF347001.1, AF346999.1, AF347011.1, AF347013.1,AF346967.1, AF346971.1, AF346975.1, AF346985.1, AF346986.1, AF347009.1,AF347012.1, AF347014.1, AF346989.1, AF347006.1, J01415.1, V00662.1,AF346966.1, AF346978.1, AF346979.1, AF346982.1, AF346983.1, AF346988.1,AF346990.1, AF346994.1, AF347008.1, X93334.1, AF346970.1, AF346972.1,AF346981.1, AF346984.1, AF346991.1, AF347010.1, AF347015.1, AF346964.1,AF346965.1, AF346993.1, AF347007.1, AF346987.1, AF346996.1, AF346968.1,AF346969.1, AF346997.1, AF346995.1, AF346963.1, AF346977.1, AF347000.1,AF346973.1, AF346976.1, AF346980.1, AF347003.1, AF346974.1, AF346992.1,AF347004.1, AF347005.1, AF347002.1, D38113.1, X93335.1, AF271371.1,L27636.1, D34614.1, L27601.1, AB017116.1, X67155.2, L27600.1, S78798.1,D88547.1, X92518.1, D14548.1, AF058696.1, AB028859.1, AJ244003.1,AJ244004.1, AJ244005.1, X73004.1, AC007993.15, Z96142.1, BC007712.1,Y11923.1, AB002449.1, Y11926.1, AB033111.1, X73003.1. HSHBF76 190 7158381-1259 15-1273 AI198543, AW027453, BF569035, BF062076, BF056301,AI694380, AW771566, AI950836, AI769655, AI800526, AI765069, BE552071,AA708811, BE645418, BF983434, AW514312, BE870149, AI804763, AI193044,AI273413, BE840116, AW504874, AA156450, BF568737, AA678373, AW369915,AW071657, BG150349, AA143141, AW369859, AW369914, AW369917, N45126,AI143564, AW196425, AW369906, AA026661, AA147579, AI248731, AW176312,BE857715, AW378548, BE840067, BE840065, AW369858, W70056, R68010,C15009, AW960647, AA564420, AA534504, AW516592, BE696667, AW168286,AW027279, W70183, BF334843, AW631008, T49357, AI248547, AI909950,R68011, BF115265, AW369857, C15008, BF847503, AW316856, AA368406,BF054931, T24692, AI653377, AI762291, AA503862, C15912, AA143381,AW316788, AI891034, R73287, D80781, AI688643, AA370097, BF351644,W57620, BE502165, AW627705, BF513704, AI418942, AI767449, AA427668,BE673340, AI342555, AW748211, AI682534, AA513358, AA026709, AA333744,AI333618, BF939494, AI660050, AI291907, AI906801, AI906791, BC008335.1,AC009000.6, AC011472.7.Description of Table 4

Table 4 provides a key to the tissue/cell source identifier codedisclosed in Table 1B 0.2, column 8. Column 1 provides the tissue/cellsource identifier code disclosed in Table 1B.2, Column 8. Columns 2-5provide a description of the tissue or cell source. Note that“Description” and “Tissue” sources (i.e. columns 2 and 3) having theprefix “a_” indicates organs, tissues, or cells derived from “adult”sources. Codes corresponding to diseased tissues are indicated in column6 with the word “disease.” The use of the word “disease” in column 6 isnon-limiting. The tissue or cell source may be specific (e.g. aneoplasm), or may be disease-associated (e.g., a tissue sample from anormal portion of a diseased organ). Furthermore, tissues and/or cellslacking the “disease” designation may still be derived from sourcesdirectly or indirectly involved in a disease state or disorder, andtherefore may have a further utility in that disease state or disorder.In numerous cases where the tissue/cell source is a library, column 7identifies the vector used to generate the library. TABLE 4 CodeDescription Tissue Organ Cell Line Disease Vector AR022 a_Heart a_HeartAR023 a_Liver a_Liver AR024 a_mammary gland a_mammary gland AR025a_Prostate a_Prostate AR026 a_small intestine a_small intestine AR027a_Stomach a_Stomach AR028 Blood B cells Blood B cells AR029 Blood Bcells activated Blood B cells activated AR030 Blood B cells restingBlood B cells resting AR031 Blood T cells activated Blood T cellsactivated AR032 Blood T cells resting Blood T cells resting AR033 brainbrain AR034 breast breast AR024 a_mammary gland a_mammary gland AR025a_Prostate a_Prostate AR026 a_small intestine a_small intestine AR035breast cancer breast cancer AR036 Cell Line CAOV3 Cell Line CAOV3 AR037cell line PA-1 cell line PA-1 AR038 cell line transformed cell linetransformed AR039 colon colon AR040 colon (9808co65R) colon (9808co65R)AR041 colon (9809co15) colon (9809co15) AR042 colon cancer colon cancerAR043 colon cancer colon cancer (9808co64R) (9808co64R) AR044 coloncancer 9809co14 colon cancer 9809co14 AR050 Donor II B Cells 24 hrsDonor II B Cells 24 hrs AR051 Donor II B Cells 72 hrs Donor II B Cells72 hrs AR052 Donor II B-Cells 24 hrs. Donor II B-Cells 24 hrs. AR053Donor II B-Cells 72 hrs Donor II B-Cells 72 hrs AR054 Donor II Resting BDonor II Resting B Cells Cells AR055 Heart Heart AR056 Human Lung HumanLung (clonetech) (clonetech) AR057 Human Mammary Human Mammary(clontech) (clontech) AR058 Human Thymus Human Thymus (clonetech)(clonetech) AR059 Jurkat (unstimulated) Jurkat (unstimulated) AR060Kidney Kidney AR061 Liver Liver AR062 Liver (Clontech) Liver (Clontech)AR063 Lymphocytes chronic Lymphocytes chronic lymphocytic leukaemialymphocytic leukaemia AR064 Lymphocytes diffuse Lymphocytes diffuselarge B large B cell lymphoma cell lymphoma AR065 Lymphocytes follicularLymphocytes follicular lymphoma lymphoma AR066 normal breast normalbreast AR067 Normal Ovarian Normal Ovarian (4004901) (4004901) AR068Normal Ovary Normal Ovary 9508G045 9508G045 AR069 Normal Ovary NormalOvary 9701G208 9701G208 AR070 Normal Ovary Normal Ovary 9806G0059806G005 AR071 Ovarian Cancer Ovarian Cancer AR072 Ovarian CancerOvarian Cancer (9702G001) (9702G001) AR073 Ovarian Cancer Ovarian Cancer(9707G029) (9707G029) AR074 Ovarian Cancer Ovarian Cancer (9804G011)(9804G011) AR075 Ovarian Cancer Ovarian Cancer (9806G019) (9806G019)AR076 Ovarian Cancer Ovarian Cancer (9807G017) (9807G017) AR077 OvarianCancer Ovarian Cancer (9809G001) (9809G001) AR078 ovarian cancer 15799ovarian cancer 15799 AR079 Ovarian Cancer Ovarian Cancer 17717AID17717AID AR080 Ovarian Cancer Ovarian Cancer 4004664B1 4004664B1 AR081Ovarian Cancer Ovarian Cancer 4005315A1 4005315A1 AR082 ovarian cancerovarian cancer 94127303 94127303 AR083 Ovarian Cancer Ovarian Cancer96069304 96069304 AR084 Ovarian Cancer Ovarian Cancer 9707G029 9707G029AR085 Ovarian Cancer Ovarian Cancer 9807G045 9807G045 AR086 ovariancancer ovarian cancer 9809G001 9809G001 AR087 Ovarian Cancer OvarianCancer 9905C032RC 9905C032RC AR088 Ovarian cancer 9907 Ovarian cancer9907 C00 3rd C00 3rd AR089 Prostate Prostate AR090 Prostate (clonetech)Prostate (clonetech) AR091 prostate cancer prostate cancer AR092prostate cancer #15176 prostate cancer #15176 AR093 prostate cancer#15509 prostate cancer #15509 AR094 prostate cancer #15673 prostatecancer #15673 AR095 Small Intestine Small Intestine (Clontech)(Clontech) AR096 Spleen Spleen AR097 Thymus T cells Thymus T cellsactivated activated AR098 Thymus T cells resting Thymus T cells restingAR099 Tonsil Tonsil AR100 Tonsil geminal center Tonsil geminal centercentroblast centroblast AR101 Tonsil germinal center Tonsil germinalcenter B cell B cell AR102 Tonsil lymph node Tonsil lymph node AR103Tonsil memory B cell Tonsil memory B cell AR104 Whole Brain Whole BrainAR105 Xenograft ES-2 Xenograft ES-2 AR106 Xenograft SW626 XenograftSW626 AR119 001: IL-2 001: IL-2 AR120 001: IL-2.1 001: IL-2.1 AR121 001:IL-2_b 001: IL-2_b AR124 002: Monocytes 002: Monocytes untreateduntreated (1 hr) (1 hr) AR125 002: Monocytes 002: Monocytes untreateduntreated (5 hrs) (5 hrs) AR126 002: Control.1C 002: Control.1C AR127002: IL2.1C 002: IL2.1C AR130 003: Placebo-treated 003: Placebo-treatedRat Rat Lacrimal Gland Lacrimal Gland AR131 003: Placebo-treated 003:Placebo-treated Rat Rat Submandibular Submandibular Gland Gland AR135004: Monocytes 004: Monocytes untreated untreated (5 hrs) (5 hrs) AR136004: Monocytes 004: Monocytes untreated untreated 1 hr 1 hr AR139 005:Placebo (48 hrs) 005: Placebo (48 hrs) AR140 006: pC4 (24 hrs) 006: pC4(24 hrs) AR141 006: pC4 (48 hrs) 006: pC4 (48 hrs) AR152 007: PHA(1 hr)007: PHA(1 hr) AR153 007: PHA(6 HRS) 007: PHA(6 HRS) AR154 007: PMA(6hrs) 007: PMA(6 hrs) AR155 008: 1449_#2 008: 1449_#2 AR161 01: A - max24 01: A - max 24 AR162 01: A - max 26 01: A - max 26 AR163 01: A - max30 01: A - max 30 AR164 01: B - max 24 01: B - max 24 AR165 01: B - max26 01: B - max 26 AR166 01: B - max 30 01: B - max 30 AR167 1449 Sample1449 Sample AR168 3T3P10 1.0 uM insulin 3T3P10 1.0 uM insulin AR1693T3P10 10 nM Insulin 3T3P10 10 nM Insulin AR170 3T3P10 10 uM insulin3T3P10 10 uM insulin AR171 3T3P10 No Insulin 3T3P10 No Insulin AR1723T3P4 3T3P4 AR173 Adipose (41892) Adipose (41892) AR174 Adipose DiabeticAdipose Diabetic (41611) (41611) AR175 Adipose Diabetic Adipose Diabetic(41661) (41661) AR176 Adipose Diabetic Adipose Diabetic (41689) (41689)AR177 Adipose Diabetic Adipose Diabetic (41706) (41706) AR178 AdiposeDiabetic Adipose Diabetic (42352) (42352) AR179 Adipose Diabetic AdiposeDiabetic (42366) (42366) AR180 Adipose Diabetic Adipose Diabetic (42452)(42452) AR181 Adipose Diabetic Adipose Diabetic (42491) (42491) AR182Adipose Normal Adipose Normal (41843) (41843) AR183 Adipose NormalAdipose Normal (41893) (41893) AR184 Adipose Normal Adipose Normal(42452) (42452) AR185 Adrenal Gland Adrenal Gland AR186 Adrenal Gland +Whole Adrenal Gland + Whole Brain Brain AR187 B7(1 hr)+ (inverted) B7(1hr)+ (inverted) AR188 Breast (18275A2B) Breast (18275A2B) AR189 Breast(4004199) Breast (4004199) AR190 Breast (4004399) Breast (4004399) AR191Breast (4004943B7) Breast (4004943B7) AR192 Breast (4005570B1) Breast(4005570B1) AR193 Breast Cancer Breast Cancer (4004127A30) (4004127A30)AR194 Breast Cancer Breast Cancer (400443A21) (400443A21) AR195 BreastCancer Breast Cancer (4004643A2) (4004643A2) AR196 Breast Cancer BreastCancer (4004710A7) (4004710A7) AR197 Breast Cancer Breast Cancer(4004943A21) (4004943A21) AR198 Breast Cancer Breast Cancer (400553A2)(400553A2) AR199 Breast Cancer Breast Cancer (9805C046R) (9805C046R)AR200 Breast Cancer Breast Cancer (9806C012R) (9806C012R) AR201 BreastCancer (ODQ Breast Cancer (ODQ 45913) 45913) AR202 Breast Cancer BreastCancer (ODQ45913) (ODQ45913) AR203 Breast Cancer Breast Cancer(ODQ4591B) (ODQ4591B) AR204 Colon Cancer (15663) Colon Cancer (15663)AR205 Colon Cancer Colon Cancer (4005144A4) (4005144A4) H0002 HumanAdult Heart Human Adult Heart Heart Uni-ZAP XR H0003 Human Adult LiverHuman Adult Liver Liver Uni-ZAP XR H0004 Human Adult Spleen Human AdultSpleen Spleen Uni-ZAP XR H0008 Whole 6 Week Old Uni-ZAP XR Embryo H0009Human Fetal Brain Uni-ZAP XR H0011 Human Fetal Kidney Human Fetal KidneyKidney Uni-ZAP XR H0012 Human Fetal Kidney Human Fetal Kidney KidneyUni-ZAP XR H0013 Human 8 Week Whole Human 8 Week Old Embryo EmbryoUni-ZAP XR Embryo H0014 Human Gall Bladder Human Gall Bladder GallBladder Uni-ZAP XR H0015 Human Gall Bladder, Human Gall Bladder GallBladder Uni-ZAP XR fraction II H0018 Human Greater Human Greater Omentumperitoneum Uni-ZAP XR Omentum, fII remake H0022 Jurkat Cells JurkatT-Cell Line Lambda ZAP II H0024 Human Fetal Lung III Human Fetal LungLung Uni-ZAP XR H0026 Namalwa Cells Namalwa B-Cell Line, EBV Lambda ZAPII immortalized H0028 Human Old Ovary Human Old Ovary Ovary pBluescriptH0029 Human Pancreas Human Pancreas Pancreas Uni-ZAP XR H0030 HumanPlacenta Uni-ZAP XR H0031 Human Placenta Human Placenta Placenta Uni-ZAPXR H0032 Human Prostate Human Prostate Prostate Uni-ZAP XR H0033 HumanPituitary Human Pituitary Uni-ZAP XR H0036 Human Adult Small Human AdultSmall Intestine Small Int. Uni-ZAP XR Intestine H0037 Human Adult SmallHuman Adult Small Intestine Small Int. pBluescript Intestine H0038 HumanTestes Human Testes Testis Uni-ZAP XR H0039 Human Pancreas Tumor HumanPancreas Tumor Pancreas disease Uni-ZAP XR H0040 Human Testes TumorHuman Testes Tumor Testis disease Uni-ZAP XR H0041 Human Fetal BoneHuman Fetal Bone Bone Uni-ZAP XR H0042 Human Adult Human Adult PulmonaryLung Uni-ZAP XR Pulmonary H0044 Human Cornea Human Cornea eye Uni-ZAP XRH0046 Human Endometrial Human Endometrial Tumor Uterus disease Uni-ZAPXR Tumor H0047 Human Fetal Liver Human Fetal Liver Liver Uni-ZAP XRH0050 Human Fetal Heart Human Fetal Heart Heart Uni-ZAP XR H0051 HumanHippocampus Human Hippocampus Brain Uni-ZAP XR H0052 Human CerebellumHuman Cerebellum Brain Uni-ZAP XR H0056 Human Umbilical Vein, HumanUmbilical Vein Umbilical vein Uni-ZAP XR Endo. remake Endothelial CellsH0057 Human Fetal Spleen Uni-ZAP XR H0059 Human Uterine Cancer HumanUterine Cancer Uterus disease Lambda ZAP II H0060 Human Macrophage HumanMacrophage Blood Cell Line pBluescript H0061 Human Macrophage HumanMacrophage Blood Cell Line pBluescript H0063 Human Thymus Human ThymusThymus Uni-ZAP XR H0068 Human Skin Tumor Human Skin Tumor Skin diseaseUni-ZAP XR H0069 Human Activated T- Activated T-Cells Blood Cell LineUni-ZAP XR Cells H0070 Human Pancreas Human Pancreas Pancreas Uni-ZAP XRH0071 Human Infant Adrenal Human Infant Adrenal Gland Adrenal glandUni-ZAP XR Gland H0075 Human Activated T- Activated T-Cells Blood CellLine Uni-ZAP XR Cells (II) H0081 Human Fetal Epithelium Human Fetal SkinSkin Uni-ZAP XR (Skin) H0082 Human Fetal Muscle Human Fetal Muscle SkMuscle Uni-ZAP XR H0083 HUMAN JURKAT Jurkat Cells Uni-ZAP XR MEMBRANEBOUND POLYSOMES H0085 Human Colon Human Colon Lambda ZAP II H0086 Humanepithelioid Epithelioid Sarcoma, muscle Sk Muscle disease Uni-ZAP XRsarcoma H0087 Human Thymus Human Thymus pBluescript H0090 Human T-CellT-Cell Lymphoma T-Cell disease Uni-ZAP XR Lymphoma H0095 Human GreaterHuman Greater Omentum peritoneum Uni-ZAP XR Omentum, RNA Remake H0097Human Adult Heart, Human Adult Heart Heart pBluescript subtracted H0098Human Adult Liver, Human Adult Liver Liver Uni-ZAP XR subtracted H0099Human Lung Cancer, Human Lung Cancer Lung pBluescript subtracted H0100Human Whole Six Human Whole Six Week Old Embryo Uni-ZAP XR Week OldEmbryo Embryo H0101 Human 7 Weeks Old Human Whole 7 Week Old EmbryoLambda ZAP II Embryo, subtracted Embryo H0102 Human Whole 6 Week HumanWhole Six Week Old Embryo pBluescript Old Embryo (II), subt Embryo H0107Human Infant Adrenal Human Infant Adrenal Gland Adrenal glandpBluescript Gland, subtracted H0111 Human Placenta, Human PlacentaPlacenta pBluescript subtracted H0121 Human Cornea, Human Cornea eyeUni-ZAP XR subtracted H0122 Human Adult Skeletal Human Skeletal MuscleSk Muscle Uni-ZAP XR Muscle H0123 Human Fetal Dura Human Fetal DuraMater Brain Uni-ZAP XR Mater H0124 Human Human Rhabdomyosarcoma SkMuscle disease Uni-ZAP XR Rhabdomyosarcoma H0125 Cem cells CyclohexamideTreated Cem, Blood Cell Line Uni-ZAP XR cyclohexamide treated Jurkat,Raji, and Supt H0129 Jurkat cells, thiouridine Jurkat Cells Uni-ZAP XRactivated, fract II H0130 LNCAP untreated LNCAP Cell Line Prostate CellLine Uni-ZAP XR H0131 LNCAP + o.3 nM R1881 LNCAP Cell Line Prostate CellLine Uni-ZAP XR H0132 LNCAP + 30 nM R1881 LNCAP Cell Line Prostate CellLine Uni-ZAP XR H0134 Raji Cells, Cyclohexamide Treated Cem, Blood CellLine Uni-ZAP XR cyclohexamide treated Jurkat, Raji, and Supt H0135 HumanSynovial Human Synovial Sarcoma Synovium Uni-ZAP XR Sarcoma H0136 SuptCells, Cyclohexamide Treated Cem, Blood Cell Line Uni-ZAP XRcyclohexamide treated Jurkat, Raji, and Supt H0140 Activated T-Cells, 8hrs. Activated T-Cells Blood Cell Line Uni-ZAP XR H0141 ActivatedT-Cells, 12 hrs. Activated T-Cells Blood Cell Line Uni-ZAP XR H0144 NineWeek Old Early 9 Wk Old Early Stage Human Embryo Uni-ZAP XR Stage HumanH0147 Human Adult Liver Human Adult Liver Liver Uni-ZAP XR H0149 7 WeekOld Early Stage Human Whole 7 Week Old Embryo Uni-ZAP XR Human,subtracted Embryo H0150 Human Epididymus Epididymis Testis Uni-ZAP XRH0151 Early Stage Human Human Fetal Liver Liver Uni-ZAP XR Liver H0154Human Fibrosarcoma Human Skin Fibrosarcoma Skin disease Uni-ZAP XR H0156Human Adrenal Gland Human Adrenal Gland Tumor Adrenal Gland diseaseUni-ZAP XR Tumor H0157 Activated T-Cells, 0 hrs, Activated T-Cells BloodCell Line Uni-ZAP XR ligation 2 H0159 Activated T-Cells, 8 hrs.,Activated T-Cells Blood Cell Line Uni-ZAP XR ligation 2 H0163 HumanSynovium Human Synovium Synovium Uni-ZAP XR H0165 Human Prostate Cancer,Human Prostate Cancer, stage Prostate disease Uni-ZAP XR Stage B2 B2H0166 Human Prostate Cancer, Human Prostate Cancer, stage Prostatedisease Uni-ZAP XR Stage B2 fraction B2 H0167 Activated T-Cells, 24 hrs.Activated T-Cells Blood Cell Line Uni-ZAP XR H0168 Human ProstateCancer, Human Prostate Cancer, stage C Prostate disease Uni-ZAP XR StageC H0169 Human Prostate Cancer, Human Prostate Cancer, stage C Prostatedisease Uni-ZAP XR Stage C fraction H0170 12 Week Old Early Twelve WeekOld Early Embryo Uni-ZAP XR Stage Human Stage Human H0171 12 Week OldEarly Twelve Week Old Early Embryo Uni-ZAP XR Stage Human, II StageHuman H0173 Human Human Cardiomyopathy Heart disease Uni-ZAP XRCardiomyopathy, RNA remake H0175 H. Adult Spleen, ziplox pSport1 H0177CAMA1Ee Cell Line CAMA1Ee Cell Line Breast Cell Line Uni-ZAP XR H0178Human Fetal Brain Human Fetal Brain Brain Uni-ZAP XR H0179 HumanNeutrophil Human Neutrophil Blood Cell Line Uni-ZAP XR H0181 HumanPrimary Breast Human Primary Breast Breast disease Uni-ZAP XR CancerCancer H0182 Human Primary Breast Human Primary Breast Breast diseaseUni-ZAP XR Cancer Cancer H0183 Human Colon Cancer Human Colon CancerColon disease Uni-ZAP XR H0187 Resting T-Cell T-Cells Blood Cell LineLambda ZAP II H0188 Human Normal Breast Human Normal Breast BreastUni-ZAP XR H0194 Human Cerebellum, Human Cerebellum Brain pBluescriptsubtracted H0196 Human Human Cardiomyopathy Heart Uni-ZAP XRCardiomyopathy, subtracted H0197 Human Fetal Liver, Human Fetal LiverLiver Uni-ZAP XR subtracted H0199 Human Fetal Liver, Human Fetal LiverLiver Uni-ZAP XR subtracted, neg clone H0200 Human Greater Human GreaterOmentum peritoneum Uni-ZAP XR Omentum, fract II remake, H0201 HumanHippocampus, Human Hippocampus Brain pBluescript subtracted H0202 JurkatCells, Cyclohexamide Treated Cem, Blood Cell Line Uni-ZAP XRcyclohexamide treated, Jurkat, Raji, and Supt subtraction H0204 HumanColon Cancer, Human Colon Cancer Colon pBluescript subtracted H0205Human Colon Cancer, Human Colon Cancer Colon pBluescript differentialH0207 LNCAP, differential LNCAP Cell Line Prostate Cell Line pBluescriptexpression H0208 Early Stage Human Human Fetal Lung Lung pBluescriptLung, subtracted H0209 Human Cerebellum, Human Cerebellum Brain Uni-ZAPXR differentially expressed H0212 Human Prostate, Human ProstateProstate pBluescript subtracted H0213 Human Pituitary, Human PituitaryUni-ZAP XR subtracted H0216 Supt cells, Cyclohexamide Treated Cem, BloodCell Line pBluescript cyclohexamide treated, Jurkat, Raji, and Suptsubtracted H0218 Activated T-Cells, 0 hrs, Activated T-Cells Blood CellLine Uni-ZAP XR subtracted H0219 Activated T-Cells, 0 hrs, ActivatedT-Cells Blood Cell Line Uni-ZAP XR differentially expressed H0220Activated T-Cells, 4 hrs, Activated T-Cells Blood Cell Line Uni-ZAP XRsubtracted H0222 Activated T-Cells, 8 hrs, Activated T-Cells Blood CellLine Uni-ZAP XR subtracted H0225 Activated T-Cells, Activated T-CellsBlood Cell Line Uni-ZAP XR 12 hrs, differentially expressed H0229 EarlyStage Human Early Stage Human Brain Brain Lambda ZAP II Brain, randomprimed H0230 Human Human Cardiomyopathy Heart disease Uni-ZAP XRCardiomyopathy, diff exp H0231 Human Colon, Human Colon pBluescriptsubtraction H0232 Human Colon, Human Colon pBluescript differentialexpression H0235 Human colon cancer, Human Colon Cancer, LiverpBluescript metaticized to liver, metasticized to liver subtractionH0239 Human Kidney Tumor Human Kidney Tumor Kidney disease Uni-ZAP XRH0241 C7MCF7 cell line, C7MCF7 Cell Line, estrogen Breast Cell LineUni-ZAP XR estrogen treated, treated subtraction H0242 Human FetalHeart, Human Fetal Heart Heart pBluescript Differential (Fetal-Specific) H0244 Human 8 Week Whole Human 8 Week Old Embryo EmbryoUni-ZAP XR Embryo, subtracted H0246 Human Fetal Liver- Human Fetal LiverLiver Uni-ZAP XR Enzyme subtraction H0249 HE7, subtracted by Human Whole7 Week Old Embryo Uni-ZAP XR hybridization with E7 Embryo cDNA H0250Human Activated Human Monocytes Uni-ZAP XR Monocytes H0251 Human HumanChondrosarcoma Cartilage disease Uni-ZAP XR Chondrosarcoma H0252 HumanOsteosarcoma Human Osteosarcoma Bone disease Uni-ZAP XR H0253 Humanadult testis, Human Adult Testis Testis Uni-ZAP XR large inserts H0254Breast Lymph node Breast Lymph Node Lymph Node Uni-ZAP XR cDNA libraryH0255 breast lymph node Breast Lymph Node Lymph Node Lambda ZAP II CDNAlibrary H0256 HL-60, unstimulated Human HL-60 Cells, Blood Cell LineUni-ZAP XR unstimulated H0257 HL-60, PMA 4 H HL-60 Cells, PMA stimulatedBlood Cell Line Uni-ZAP XR 4 H H0261 H. cerebellum, Enzyme HumanCerebellum Brain Uni-ZAP XR subtracted H0263 human colon cancer HumanColon Cancer Colon disease Lambda ZAP II H0264 human tonsils HumanTonsil Tonsil Uni-ZAP XR H0265 Activated T-Cell T-Cells Blood Cell LineUni-ZAP XR (12 hs)/Thiouridine labelledEco H0266 Human MicrovascularHMEC Vein Cell Line Lambda ZAP II Endothelial Cells, fract. A H0267Human Microvascular HMEC Vein Cell Line Lambda ZAP II Endothelial Cells,fract. B H0268 Human Umbilical Vein HUVE Cells Umbilical vein Cell LineLambda ZAP II Endothelial Cells, fract. A H0269 Human Umbilical VeinHUVE Cells Umbilical vein Cell Line Lambda ZAP II Endothelial Cells,fract. B H0270 HPAS (human pancreas, Human Pancreas Pancreas Uni-ZAP XRsubtracted) H0271 Human Neutrophil, Human Neutrophil - Blood Cell LineUni-ZAP XR Activated Activated H0272 HUMAN TONSILS, Human Tonsil TonsilUni-ZAP XR FRACTION 2 H0275 Human Infant Adrenal Human Infant AdrenalGland Adrenal gland pBluescript Gland, Subtracted H0280 K562 + PMA (36hrs) K562 Cell line cell line Cell Line ZAP Express H0284 Human OB MG63Human Osteoblastoma MG63 Bone Cell Line Uni-ZAP XR control fraction Icell line H0286 Human OB MG63 Human Osteoblastoma MG63 Bone Cell LineUni-ZAP XR treated (10 nM E2) cell line fraction I H0288 Human OB HOSHuman Osteoblastoma HOS Bone Cell Line Uni-ZAP XR control fraction Icell line H0290 Human OB HOS treated Human Osteoblastoma HOS Bone CellLine Uni-ZAP XR (1 nM E2) fraction I cell line H0292 Human OB HOStreated Human Osteoblastoma HOS Bone Cell Line Uni-ZAP XR (10 nM E2)fraction I cell Line H0293 WI 38 cells Uni-ZAP XR H0294 Amniotic Cells -TNF Amniotic Cells - TNF Placenta Cell Line Uni-ZAP XR induced inducedH0295 Amniotic Cells - Amniotic Cells - Primary Placenta Cell LineUni-ZAP XR Primary Culture Culture H0300 CD34 positive cells CD34Positive Cells Cord Blood ZAP Express (Cord Blood) H0305 CD34 positivecells CD34 Positive Cells Cord Blood ZAP Express (Cord Blood) H0306 CD34depleted Buffy CD34 Depleted Buffy Coat Cord Blood ZAP Express Coat(Cord Blood) (Cord Blood) H0309 Human Chronic Synovium, Chronic Synoviumdisease Uni-ZAP XR Synovitis Synovitis/Osteoarthritis H0310 humancaudate nucleus Brain Brain Uni-ZAP XR H0318 HUMAN B CELL Human B CellLymphoma Lymph Node disease Uni-ZAP XR LYMPHOMA H0327 human corpuscolosum Human Corpus Callosum Brain Uni-ZAP XR H0328 human ovariancancer Ovarian Cancer Ovary disease Uni-ZAP XR H0329 DermatofibrosarcomaDermatofibrosarcoma Skin disease Uni-ZAP XR Protuberance ProtuberansH0331 Hepatocellular Tumor Hepatocellular Tumor Liver disease Lambda ZAPII H0333 Hemangiopericytoma Hemangiopericytoma Blood vessel diseaseLambda ZAP II H0334 Kidney cancer Kidney Cancer Kidney disease Uni-ZAPXR H0339 Duodenum Duodenum Uni-ZAP XR H0340 Corpus Callosum CorpusCollosum-93052 Uni-ZAP XR H0341 Bone Marrow Cell Line Bone Marrow CellLine Bone Marrow Cell Line Uni-ZAP XR (RS4; 11) RS4; 11 H0343 stomachcancer (human) Stomach Cancer - 5383A disease Uni-ZAP XR (human) H0344Adipose tissue (human) Adipose - 6825A (human) Uni-ZAP XR H0345 SKINSkin - 4000868H Skin Uni-ZAP XR H0346 Brain-medulloblastoma Brain(Medulloblastoma)- Brain disease Uni-ZAP XR 9405C006R H0349 human adultliver Human Adult Liver Liver pCMVSport 1 cDNA library H0350 Human FetalLiver, Human Fetal Liver, mixed Liver Uni-ZAP XR mixed 10 & 14 week10&14 Week H0351 Glioblastoma Glioblastoma Brain disease Uni-ZAP XRH0352 wilm''s tumor Wilm''s Tumor disease Uni-ZAP XR H0354 HumanLeukocytes Human Leukocytes Blood Cell Line pCMVSport 1 H0355 HumanLiver Human Liver, normal Adult pCMVSport 1 H0357 H. Normalized FetalHuman Fetal Liver Liver Uni-ZAP XR Liver, II H0366 L428 cell line L428ZAP Express H0369 H. Atrophic Atrophic Endometrium and Uni-ZAP XREndometrium myometrium H0370 H. Lymph node breast Lymph node with Met.Breast disease Uni-ZAP XR Cancer Cancer H0373 Human Heart Human AdultHeart Heart pCMVSport 1 H0374 Human Brain Human Brain pCMVSport 1 H0375Human Lung Human Lung pCMVSport 1 H0379 Human Tongue, frac 1 HumanTongue pSport1 H0380 Human Tongue, frac 2 Human Tongue pSport1 H0381Bone Cancer Bone Cancer disease Uni-ZAP XR H0383 Human Prostate BPH,Human Prostate BPH Uni-ZAP XR re-excision H0386 Leukocyte and Lung; 4Human Leukocytes Blood Cell Line pCMVSport 1 screens H0388 HumanRejected Human Rejected Kidney disease pBluescript Kidney, 704re-excision H0390 Human Amygdala Human Amygdala Depression diseasepBluescript Depression, re-excision H0391 H. Meniingima, M6 HumanMeningima brain pSport1 H0392 H. Meningima, M1 Human Meningima brainpSport1 H0393 Fetal Liver, subtraction Human Fetal Liver LiverpBluescript II H0395 A1-CELL LINE Redd-Sternberg cell ZAP Express H0400Human Striatum Human Brain, Striatum Brain Lambda ZAP II Depression,re-rescue Depression H0401 Human Pituitary, Human Pituitary pBluescriptsubtracted V H0402 CD34 depleted Buffy CD34 Depleted Buffy Coat CordBlood ZAP Express Coat (Cord Blood), re- (Cord Blood) excision H0403 H.Umbilical Vein HUVE Cells Umbilical vein Cell Line Uni-ZAP XREndothelial Cells, IL4 induced H0406 H Amygdala Human AmygdalaDepression Uni-ZAP XR Depression, subtracted H0408 Human kidney Cortex,Human Kidney Cortex pBluescript subtracted H0409 H. Striatum Depression,Human Brain, Striatum Brain pBluescript subtracted Depression H0411 HFemale Bladder, Human Female Adult Bladder Bladder pSport1 Adult H0412Human umbilical vein HUVE Cells Umbilical vein Cell Line pSport1endothelial cells, IL-4 induced H0413 Human Umbilical Vein HUVE CellsUmbilical vein Cell Line pSport1 Endothelial Cells, uninduced H0414Ovarian Tumor I, Ovarian Tumor, OV5232 Ovary disease pSport1 OV5232H0415 H. Ovarian Tumor, II, Ovarian Tumor, OV5232 Ovary diseasepCMVSport 2.0 OV5232 H0416 Human Neutrophils, Human Neutrophil - BloodCell Line pBluescript Activated, re-excision Activated H0417 HumanPituitary, Human Pituitary pBluescript subtracted VIII H0419 BoneCancer, re- Bone Cancer Uni-ZAP XR excision H0421 Human Bone Marrow,Bone Marrow pBluescript re-excision H0422 T-Cell PHA 16 hrs T-CellsBlood Cell Line pSport1 H0423 T-Cell PHA 24 hrs T-Cells Blood Cell LinepSport1 H0424 Human Pituitary, subt Human Pituitary pBluescript IX H0427Human Adipose Human Adipose, left pSport1 hiplipoma H0428 Human OvaryHuman Ovary Tumor Ovary pSport1 H0429 K562 + PMA (36 hrs), K562 Cellline cell line Cell Line ZAP Express re-excisision H0431 H. KidneyMedulla, re- Kidney medulla Kidney pBluescript excision H0433 HumanUmbilical Vein HUVE Cells Umbilical vein Cell Line pBluescriptEndothelial cells, frac B, re-excision H0435 Ovarian Tumor 10-3-95Ovarian Tumor, OV350721 Ovary pCMVSport 2.0 H0436 Resting T-Cell T-CellsBlood Cell Line pSport1 Library, II H0437 H Umbilical Vein HUVE CellsUmbilical vein Cell Line Lambda ZAP II Endothelial Cells, frac A,re-excision H0438 H. Whole Brain #2, re- Human Whole Brain #2 ZAPExpress excision H0439 Human Eosinophils Eosinophils pBluescript H0441H. Kidney Cortex, Kidney cortex Kidney pBluescript subtracted H0444Spleen metastic Spleen, Metastic malignant Spleen disease pSport1melanoma melanoma H0445 Spleen, Chronic Human Spleen, CLL Spleen diseasepSport1 lymphocytic leukemia H0449 CD34 + cell, I CD34 positive cellspSport1 H0450 CD34 + cells, II CD34 positive cells pCMVSport 2.0 H0453H. Kidney Pyramid, Kidney pyramids Kidney pBluescript subtracted H0455H. Striatum Depression, Human Brain, Striatum Brain pBluescript subtDepression H0457 Human Eosinophils Human Eosinophils pSport1 H0458CD34 + cell, I, frac II CD34 positive cells pSport1 H0459 CD34 + cells,II, CD34 positive cells pCMVSport 2.0 FRACTION 2 H0461 H. KidneyMedulla, Kidney medulla Kidney pBluescript subtracted H0477 HumanTonsil, Lib 3 Human Tonsil Tonsil pSport1 H0478 Salivary Gland, Lib 2Human Salivary Gland Salivary gland pSport1 H0479 Salivary Gland, Lib 3Human Salivary Gland Salivary gland pSport1 H0483 Breast Cancer cellline, Breast Cancer Cell line, pSport1 MDA 36 MDA 36 H0484 Breast CancerCell line, Breast Cancer Cell line, pSport1 angiogenic Angiogenic, 36T3H0485 Hodgkin''s Lymphoma I Hodgkin''s Lymphoma I disease pCMVSport 2.0H0486 Hodgkin''s Lymphoma Hodgkin''s Lymphoma II disease pMVSport 2.0 IIH0487 Human Tonsils, lib I Human Tonsils pCMVSport 2.0 H0488 HumanTonsils, Lib 2 Human Tonsils pCMVSport 2.0 H0492 HL-60, RA 4 h, HL-60Cells, RA stimulated Blood Cell Line Uni-ZAP XR Subtracted for 4 H H0493HL-60, PMA 1 d, HL-60 Cells, PMA stimulated Blood Cell Line Uni-ZAP XRsubtracted for 1 day H0494 Keratinocyte Keratinocyte pCMVSport 2.0 H0497HEL cell line HEL cell line HEL 92.1.7 pSport1 H0505 Human Astrocyte.Human Astrocyte pSport1 H0506 Ulcerative Colitis Colon Colon pSport1H0509 Liver, Hepatoma Human Liver, Hepatoma, Liver disease pCMVSport 3.0patient 8 H0510 Human Liver, normal Human Liver, normal, Patient LiverpCMVSport 3.0 # 8 H0518 pBMC stimulated w/ pBMC stimulated with polypCMVSport 3.0 poly I/C I/C H0519 NTERA2, control NTERA2, TeratocarcinomapCMVSport 3.0 cell line H0520 NTERA2 + retinoic NTERA2, TeratocarcinomapSport1 acid, 14 days cell line H0521 Primary Dendritic Cells, PrimaryDendritic cells pCMVSport 3.0 lib 1 H0522 Primary Dendritic PrimaryDendritic cells pCMVSport 3.0 cells, frac 2 H0528 Poly[I]/Poly[C] NormalPoly[I]/Poly[C] Normal Lung pCMVSport 3.0 Lung Fibroblasts FibroblastsH0529 Myoloid Progenitor Cell TF-1 Cell Line; Myoloid pCMVSport 3.0 Lineprogenitor cell line H0530 Human Dermal Human Dermal Endothelial pSport1Endothelial Cells; untreated Cells, untreated H0535 Human ovary tumorcell Ovarian Tumor, OV350721 Ovary disease pSport1 OV350721 H0538 MerkelCells Merkel cells Lymph node pSport1 H0539 Pancreas Islet Cell PancreasIslet Cell Tumour Pancreas disease pSport1 Tumor H0540 Skin, burnedSkin, leg burned Skin pSport1 H0542 T Cell helper I Helper T cellpCMVSport 3.0 H0543 T cell helper II Helper T cell pCMVSport 3.0 H0544Human endometrial Human endometrial stromal pCMVSport 3.0 stromal cellscells H0545 Human endometrial Human endometrial stromal pCMVSport 3.0stromal cells-treated cells-treated with proge with progesterone H0546Human endometrial Human endometrial stromal pCMVSport 3.0 stromalcells-treated cells-treated with estra with estradiol H0547 NTERA2NTERA2, Teratocarcinoma pSport1 teratocarcinoma cell cell line line +retinoic acid (14 days) H0549 H. Epididiymus, caput Human Epididiymus,caput Uni-ZAP XR & corpus and corpus H0550 H. Epididiymus, cauda HumanEpididiymus, cauda Uni-ZAP XR H0551 Human Thymus Stromal Human ThymusStromal pCMVSport 3.0 Cells Cells H0553 Human Placenta Human PlacentapCMVSport 3.0 H0555 Rejected Kidney, lib 4 Human Rejected Kidney Kidneydisease pCMVSport 3.0 H0556 Activated T- T-Cells Blood Cell Line Uni-ZAPXR cell(12 h)/Thiouridine- re-excision H0559 HL-60, PMA 4 H, re- HL-60Cells, PMA stimulated Blood Cell Line Uni-ZAP XR excision 4 H H0560 KMH2KMH2 pCMVSport 3.0 H0561 L428 L428 pCMVSport 3.0 H0562 Human FetalBrain, Human Fetal Brain pCMVSport 2.0 normalized c5-11-26 H0563 HumanFetal Brain, Human Fetal Brain pCMVSport 2.0 normalized 50021F H0565HUman Fetal Brain, Human Fetal Brain pCMVSport 2.0 normalized 100024FH0566 Human Fetal Human Fetal Brain pCMVSport 2.0 Brain, normalized c50FH0567 Human Fetal Brain, Human Fetal Brain pCMVSport 2.0 normalizedA5002F H0569 Human Fetal Brain, Human Fetal Brain pCMVSport 2.0normalized CO H0570 Human Fetal Brain, Human Fetal Brain pCMVSport 2.0normalized C500H H0571 Human Fetal Brain, Human Fetal Brain pCMVSport2.0 normalized C500HE H0572 Human Fetal Brain, Human Fetal BrainpCMVSport 2.0 normalized AC5002 H0574 Hepatocellular Tumor;Hepatocellular Tumor Liver disease Lambda ZAP II re-excision H0575 HumanAdult Human Adult Pulmonary Lung Uni-ZAP XR Pulmonary; re-excision H0576Resting T-Cell; re- T-Cells Blood Cell Line Lambda ZAP II excision H0580Dendritic cells, pooled Pooled dendritic cells pCMVSport 3.0 H0581 HumanBone Marrow, Human Bone Marrow Bone Marrow pCMVSport 3.0 treated H0583 BCell lymphoma B Cell Lymphoma B Cell disease pCMVSport 3.0 H0584Activated T-cells, 24 hrs, Activated T-Cells Blood Cell Line Uni-ZAP XRre-excision H0585 Activated T-Cells, 12 hrs, Activated T-Cells BloodCell Line Uni-ZAP XR re-excision H0586 Healing groin wound, healinggroin wound, 6.5 groin disease pCMVSport 3.0 6.5 hours post incisionhours post incision - 2/ H0587 Healing groin wound; Groin-Feb. 19, 1997groin disease pCMVSport 3.0 7.5 hours post incision H0589 CD34 positivecells CD34 Positive Cells Cord Blood ZAP Express (cord blood), re-exH0590 Human adult small Human Adult Small Intestine Small Int. Uni-ZAPXR intestine, re-excision H0591 Human T-cell T-Cell Lymphoma T-Celldisease Uni-ZAP XR lymphoma; re-excision H0592 Healing groin wound - HGSwound healing project; disease pCMVSport 3.0 zero hr post-incisionabdomen (control) H0593 Olfactory Olfactory epithelium from pCMVSport3.0 epithelium; nasalcavity roof of left nasal cacit H0594 Human LungCancer; re- Human Lung Cancer Lung disease Lambda ZAP II excision H0595Stomach cancer Stomach Cancer - 5383A disease Uni-ZAP XR (human);re-excision (human) H0596 Human Colon Human Colon Cancer Colon LambdaZAP II Cancer; re-excision H0597 Human Colon; re- Human Colon Lambda ZAPII excision H0598 Human Stomach; re- Human Stomach Stomach Uni-ZAP XRexcision H0599 Human Adult Heart; re- Human Adult Heart Heart Uni-ZAP XRexcision H0600 Healing Abdomen Abdomen disease pCMVSport 3.0 wound;70&90 min post incision H0601 Healing Abdomen Abdomen disease pCMVSport3.0 Wound; 15 days post incision H0602 Healing Abdomen Abdomen diseasepCMVSport 3.0 Wound; 21&29 days post incision H0604 Human Pituitary, re-Human Pituitary pBluescript excision H0606 Human Primary Breast HumanPrimary Breast Breast disease Uni-ZAP XR Cancer; re-excision CancerH0607 H. Leukocytes, H. Leukocytes pCMVSport 1 normalized cot 50A3 H0610H. Leukocytes, H. Leukocytes pCMVSport 1 normalized cot 5A H0611 H.Leukocytes, H. Leukocytes pCMVSport 1 normalized cot 500 B H0612 H.Leukocytes, H. Leukocytes pCMVSport 1 normalized cot 50 B H0613 H.Leukocytes, H. Leukocytes pCMVSport 1 normalized cot 5B H0614 H.Leukocytes, H. Leukocytes pCMVSport 1 normalized cot 500 A H0615 HumanOvarian Cancer Ovarian Cancer Ovary disease Uni-ZAP XR Reexcision H0616Human Testes, Human Testes Testis Uni-ZAP XR Reexcision H0617 HumanPrimary Breast Human Primary Breast Breast disease Uni-ZAP XR CancerReexcision Cancer H0618 Human Adult Testes, Human Adult Testis TestisUni-ZAP XR Large Inserts, Reexcision H0619 Fetal Heart Human Fetal HeartHeart Uni-ZAP XR H0620 Human Fetal Kidney; Human Fetal Kidney KidneyUni-ZAP XR Reexcision H0622 Human Pancreas Human Pancreas Tumor Pancreasdisease Uni-ZAP XR Tumor; Reexcision H0623 Human Umbilical Vein; HumanUmbilical Vein Umbilical vein Uni-ZAP XR Reexcision Endothelial CellsH0624 12 Week Early Stage Twelve Week Old Early Embryo Uni-ZAP XR HumanII; Reexcision Stage Human H0625 Ku 812F Basophils Line Ku 812FBasophils pSport1 H0626 Saos2 Cells; Untreated Saos2 Cell Line;Untreated pSport1 H0627 Saos2 Cells; Vitamin Saos2 Cell Line; Vitamin D3pSport1 D3 Treated Treated H0628 Human Pre- Human Pre-DifferentiatedUni-ZAP XR Differentiated Adipocytes Adipocytes H0630 Human HumanNormalized leukocyte pCMVSport 1 Leukocytes, normalized control #4 H0631Saos2, Dexamethosome Saos2 Cell Line; pSport1 Treated DexamethosomeTreated H0632 Hepatocellular Hepatocellular Tumor Liver Lambda ZAP IITumor; re-excision H0633 Lung Carcinoma A549 TNFalpha activated A549-disease pSport1 TNFalpha activated Lung Carcinoma H0634 Human TestesTumor, Human Testes Tumor Testis disease Uni-ZAP XR re-excision H0635Human Activated T- Activated T-Cells Blood Cell Line Uni-ZAP XR Cells,re-excision H0637 Dendritic Cells From Dentritic cells from CD34 pSport1CD34 Cells cells H0638 CD40 activated CD40 activated monocyte pSport1monocyte dendridic dendridic cells cells H0641 LPS activated derived LPSactivated monocyte pSport1 dendritic cells derived dendritic cells H0642Hep G2 Cells, lambda Hep G2 Cells Other library H0643 Hep G2 Cells, PCRHep G2 Cells Other library H0644 Human Placenta (re- Human PlacentaPlacenta Uni-ZAP XR excision) H0645 Fetal Heart, re-excision Human FetalHeart Heart Uni-ZAP XR H0646 Lung, Cancer (4005313 Metastatic squamouscell pSport1 A3): Invasive Poorly lung carcinoma, poorly diDifferentiated Lung Adenocarcinoma, H0647 Lung, Cancer (4005163 Invasivepoorly differentiated disease pSport1 B7): Invasive, Poorly lungadenocarcinoma Diff. Adenocarcinoma, Metastatic H0648 Ovary, Cancer:Papillary Cstic neoplasm of disease pSport1 (4004562 B6) Papillary lowmalignant potentia Serous Cystic Neoplasm, Low Malignant Pot H0649 Lung,Normal: Normal Lung pSport1 (4005313 B1) H0650 B-Cells B-Cells pCMVSport3.0 H0651 Ovary, Normal: Normal Ovary pSport1 (9805C040R) H0652 Lung,Normal: Normal Lung pSport1 (4005313 B1) H0653 Stromal Cells StromalCells pSport1 H0656 B-cells (unstimulated) B-cells (unstimulated)pSport1 H0657 B-cells (stimulated) B-cells (stimulated) pSport1 H0658Ovary, Cancer 9809C332- Poorly Ovary & disease pSport1 (9809C332):Poorly differentiate Fallopian Tubes differentiated adenocarcinoma H0659Ovary, Cancer Grade II Papillary Carcinoma, Ovary disease pSport1(15395A1F): Grade II Ovary Papillary Carcinoma H0660 Ovary, Cancer:Poorly differentiated disease pSport1 (15799A1F) Poorly carcinoma, ovarydifferentiated carcinoma H0661 Breast, Cancer: Breast cancer diseasepSport1 (4004943 A5) H0662 Breast, Normal: Normal Breast - BreastpSport1 (4005522B2) #4005522(B2) H0663 Breast, Cancer: Breast Cancer -Breast disease pSport1 (4005522 A2) #4005522(A2) H0664 Breast, Cancer:Breast Cancer Breast disease pSport1 (9806C012R) H0665 Stromal cells3.88 Stromal cells 3.88 pSport1 H0666 Ovary, Cancer: Ovarian Cancer,Sample disease pSport1 (4004332 A2) #4004332A2 H0667 Stromal Stromalcell(HBM 3.18) pSport1 cells(HBM3.18) H0668 stromal cell clone 2.5stromal cell clone 2.5 pSport1 H0669 Breast, Cancer: Breast Cancer(4005385A2) Breast pSport1 (4005385 A2) H0670 Ovary, Cancer(4004650Ovarian Cancer - 4004650A3 pSport1 A3): Well- DifferentiatedMicropapillary Serous Carcinoma H0671 Breast, Cancer: Breast Cancer-Sample # pSport1 (9802C02OE) 9802C02OE H0672 Ovary, Cancer: OvarianCancer(4004576A8) Ovary pSport1 (4004576 A8) H0673 Human ProstateCancer, Human Prostate Cancer, stage Prostate Uni-ZAP XR Stage B2;re-excision B2 H0674 Human Prostate Cancer, Human Prostate Cancer, stageC Prostate Uni-ZAP XR Stage C; re-excission H0675 Colon, Cancer: ColonCancer 9808C064R pCMVSport 3.0 (9808C064R) H0676 Colon, Cancer: ColonCancer 9808C064R pCMVSport 3.0 (9808C064R)-total RNA H0677 TNFRdegenerate oligo B-Cells PCRII H0682 Serous Papillary serous papillarypCMVSport 3.0 Adenocarcinoma adenocarcinoma (9606G304SPA3B) H0683Ovarian Serous Serous papillary pCMVSport 3.0 Papillary adenocarcinoma,stage 3C Adenocarcinoma (9804G01 H0684 Serous Papillary OvarianCancer-9810G606 Ovaries pCMVSport 3.0 Adenocarcinoma H0685Adenocarcinoma of Adenocarcinoma of Ovary, pCMVSport 3.0 Ovary, HumanCell Human Cell Line, # OVCAR- Line, # OVCAR-3 H0686 Adenocarcinoma ofAdenocarcinoma of Ovary, pCMVSport 3.0 Ovary, Human Cell Human CellLine, # SW-626 Line H0687 Human normal Human normal Ovary pCMVSport 3.0ovary(#9610G215) ovary(#9610G215) H0688 Human Ovarian Human OvarianpCMVSport 3.0 Cancer(#9807G017) cancer(#9807G017), mRNA from Maura RuH0689 Ovarian Cancer Ovarian Cancer, #9806G019 pCMVSport 3.0 H0690Ovarian Cancer, # Ovarian Cancer, #9702G001 pCMVSport 3.0 9702G001 H0692BLyS Receptor from B Cell Lymphoma B Cell pCMVSport 3.0 ExpressionCloning H0693 Normal Prostate Normal Prostate Tissue # pCMVSport 3.0#ODQ3958EN ODQ3958EN H0694 Prostate gland Prostate gland, prostate glandpCMVSport 3.0 adenocarcinoma adenocarcinoma, mod/diff, gleason H0695mononucleocytes from mononucleocytes from pCMVSport 3.0 patient patientat Shady Grove Hospit N0006 Human Fetal Brain Human Fetal Brain S0001Brain frontal cortex Brain frontal cortex Brain Lambda ZAP II S0002Monocyte activated Monocyte-activated blood Cell Line Uni-ZAP XR S0003Human Osteoclastoma Osteoclastoma bone disease Uni-ZAP XR S0004 ProstateProstate BPH Prostate Lambda ZAP II S0005 Heart Heart-left ventricleHeart pCDNA S0006 Neuroblastoma Human Neural Blastoma disease pCDNAS0007 Early Stage Human Human Fetal Brain Uni-ZAP XR Brain S0010 HumanAmygdala Amygdala Uni-ZAP XR S0011 STROMAL - Osteoclastoma bone diseaseUni-ZAP XR OSTEOCLASTOMA S0014 Kidney Cortex Kidney cortex KidneyUni-ZAP XR S0015 Kidney medulla Kidney medulla Kidney Uni-ZAP XR S0022Human Osteoclastoma Osteoclastoma Stromal Cells Uni-ZAP XR StromalCells - unamplified S0026 Stromal cell TF274 stromal cell Bone marrowCell Line Uni-ZAP XR S0027 Smooth muscle, serum Smooth muscle PulmanaryCell Line Uni-ZAP XR treated artery S0028 Smooth muscle, control Smoothmuscle Pulmanary Cell Line Uni-ZAP XR artery S0029 brain stem Brain stembrain Uni-ZAP XR S0031 Spinal cord Spinal cord spinal cord Uni-ZAP XRS0032 Smooth muscle-ILb Smooth muscle Pulmanary Cell Line Uni-ZAP XRinduced artery S0036 Human Substantia Nigra Human Substantia NigraUni-ZAP XR S0037 Smooth muscle, IL1b Smooth muscle Pulmanary Cell LineUni-ZAP XR induced artery S0038 Human Whole Brain #2 - Human Whole Brain#2 ZAP Express Oligo dT >1.5 Kb S0040 Adipocytes Human Adipocytes fromUni-ZAP XR Osteoclastoma S0042 Testes Human Testes ZAP Express S0044Prostate BPH prostate BPH Prostate disease Uni-ZAP XR S0045 Endothelialcells-control Endothelial cell endothelial cell- Cell Line Uni-ZAP XRlung S0046 Endothelial-induced Endothelial cell endothelial cell- CellLine Uni-ZAP XR lung S0049 Human Brain, Striatum Human Brain, StriatumUni-ZAP XR S0050 Human Frontal Cortex, Human Frontal Cortex, diseaseUni-ZAP XR Schizophrenia Schizophrenia S0051 Human Human Hypothalamus,disease Uni-ZAP XR Hypothalmus, Schizophrenia Schizophrenia S0052neutrophils control human neutrophils blood Cell Line Uni-ZAP XR S0053Neutrophils IL-1 and human neutrophil induced blood Cell Line Uni-ZAP XRLPS induced S0106 STRIATUM BRAIN disease Uni-ZAP XR DEPRESSION S0110Brain Amygdala Brain disease Uni-ZAP XR Depression S0112 HypothalamusBrain Uni-ZAP XR S0114 Anergic T-cell Anergic T-cell Cell Line Uni-ZAPXR S0116 Bone marrow Bone marrow Bone marrow Uni-ZAP XR S0118 Smoothmuscle control 2 Smooth muscle Pulmanary Cell Line Uni-ZAP XR arteryS0124 Smooth muscle-edited A Smooth muscle Pulmanary Cell Line Uni-ZAPXR artery S0126 Osteoblasts Osteoblasts Knee Cell Line Uni-ZAP XR S0132Epithelial-TNFa and Airway Epithelial Uni-ZAP XR INF induced S0134Apoptotic T-cell apoptotic cells Cell Line Uni-ZAP XR S0136 PERM TF274stromal cell Bone marrow Cell Line Lambda ZAP II S0140 eosinophil-IL5induced eosinophil lung Cell Line Uni-ZAP XR S0142 Macrophage-oxLDLmacrophage-oxidized LDL blood Cell Line Uni-ZAP XR treated S0144Macrophage (GM-CSF Macrophage (GM-CSF Uni-ZAP XR treated) treated) S0146prostate-edited prostate BPH Prostate Uni-ZAP XR S0148 Normal ProstateProstate prostate Uni-ZAP XR S0150 LNCAP prostate cell LNCAP Cell LineProstate Cell Line Uni-ZAP XR line S0152 PC3 Prostate cell line PC3prostate cell line Uni-ZAP XR S0176 Prostate, normal, Prostate prostateUni-ZAP XR subtraction I S0182 Human B Cell 8866 Human B-Cell 8866Uni-ZAP XR S0188 Prostate, BPH, Lib 2 Human Prostate BPH disease pSport1S0192 Synovial Fibroblasts Synovial Fibroblasts pSport1 (control) S0194Synovial hypoxia Synovial Fibroblasts pSport1 S0196 Synovial IL-1/TNFSynovial Fibroblasts pSport1 stimulated S0206 Smooth Muscle- Smoothmuscle Pulmanary Cell Line pBluescript HASTE normalized artery S0208Messangial cell, frac 1 Messangial cell pSport1 S0210 Messangial cell,frac 2 Messangial cell pSport1 S0212 Bone Marrow Stromal Bone MarrowStromal pSport1 Cell, untreated Cell, untreated S0214 HumanOsteoclastoma, Osteoclastoma bone disease Uni-ZAP XR re-excision S0216Neutrophils IL-1 and human neutrophil induced blood Cell Line Uni-ZAP XRLPS induced S0218 Apoptotic T-cell, re- apoptotic cells Cell LineUni-ZAP XR excision S0220 H. hypothalamus, frac Hypothalamus Brain ZAPExpress A; re-excision S0222 H. Frontal H. Brain, Frontal Cortex, Braindisease Uni-ZAP XR cortex, epileptic; re- Epileptic excision S0242Synovial Fibroblasts Synovial Fibroblasts pSport1 (Il1/TNF), subt S0250Human Osteoblasts II Human Osteoblasts Femur disease pCMVSport 2.0 S0260Spinal Cord, re-excision Spinal cord spinal cord Uni-ZAP XR S0276Synovial hypoxia-RSF Synovial fobroblasts Synovial tissue pSport1subtracted (rheumatoid) S0278 H Macrophage (GM- Macrophage (GM-CSFUni-ZAP XR CSF treated), re- treated) excision S0280 Human AdiposeTissue, Human Adipose Tissue Uni-ZAP XR re-excision S0282 Brain FrontalCortex, Brain frontal cortex Brain Lambda ZAP II re-excision S0292Osteoarthritis (OA-4) Human Osteoarthritic Bone disease pSport1Cartilage S0294 Larynx tumor Larynx tumor Larynx, vocal disease pSport1cord S0298 Bone marrow Bone marrow Bone marrow pSport1 stroma, treatedstroma, treatedSB S0300 Frontal Frontal Lobe Brain Uni-ZAP XR lobe,dementia; re- dementia/Alzheimer''s excision S0306 Larynx normal #10261-273 Larynx normal pSport1 S0308 Spleen/normal Spleen normal pSport1S0310 Normal trachea Normal trachea pSport1 S0312 Human Humanosteoarthritic disease pSport1 osteoarthritic; fraction II cartilageS0314 Human Human osteoarthritic disease pSport1 osteoarthritis;fraction I cartilage S0322 Siebben Polyposis Siebben Polyposis pSport1S0328 Palate carcinoma Palate carcinoma Uvula disease pSport1 S0330Palate normal Palate normal Uvula pSport1 S0332 Pharynx carcinomaPharynx carcinoma Hypopharynx pSport1 S0340 Human Osteoarthritic Humanosteoarthritic disease pSport1 Cartilage Fraction IV cartilage S0342Adipocytes; re-excision Human Adipocytes from Uni-ZAP XR OsteoclastomaS0344 Macrophage-oxLDL; macrophage-oxidized LDL blood Cell Line Uni-ZAPXR re-excision treated S0346 Human Amygdala; re- Amygdala Uni-ZAP XRexcision S0350 Pharynx Carcinoma Pharynx carcinoma Hypopharynx diseasepSport1 S0352 Larynx Carcinoma Larynx carcinoma disease pSport1 S0354Colon Normal II Colon Normal Colon pSport1 S0356 Colon Carcinoma ColonCarcinoma Colon disease pSport1 S0358 Colon Normal III Colon NormalColon pSport1 S0360 Colon Tumor II Colon Tumor Colon disease pSport1S0362 Human Gastrocnemius Gastrocnemius muscle pSport1 S0364 HumanQuadriceps Quadriceps muscle pSport1 S0366 Human Soleus Soleus MusclepSport1 S0370 Larynx carcinoma II Larynx carcinoma disease pSport1 S0372Larynx carcinoma III Larynx carcinoma disease pSport1 S0374 Normal colonNormal colon pSport1 S0376 Colon Tumor Colon Tumor disease pSport1 S0378Pancreas normal PCA4 Pancreas Normal PCA4 No pSport1 No S0380 PancreasTumor PCA4 Pancreas Tumor PCA4 Tu disease pSport1 Tu S0382 Larynxcarcinoma IV Larynx carcinoma disease pSport1 S0384 Tongue carcinomaTongue carcinoma disease pSport1 S0386 Human Whole Brain, Whole brainBrain ZAP Express re-excision S0388 Human Human Hypothalamus, diseaseUni-ZAP XR Hypothalamus, schizophrenia, Schizophrenia re-excision S0390Smooth muscle, control; Smooth muscle Pulmanary Cell Line Uni-ZAP XRre-excision artery S0392 Salivary Gland Salivary gland; normal pSport1S0394 Stomach; normal Stomach; normal pSport1 S0398 Testis; normalTestis; normal pSport1 S0404 Rectum normal Rectum, normal pSport1 S0406Rectum tumour Rectum tumour pSport1 S0408 Colon, normal Colon, normalpSport1Description of Table 5

Table 5 provides a key to the OMIM reference identification numbersdisclosed in Table 1B.1 OMIM reference identification numbers (Column 1)were derived from Online Mendelian Inheritance in Man (Online MendelianInheritance in Man, OMIM. McKusick-Nathans Institute of GeneticMedicine, Johns Hopkins University (Baltimore, Md.) and National CenterFor Biotechnology Information, National Library of Medicine, (Bethesda,Md.) 2000. World Wide Web URL: http://www.ncbi.nlm.nih.gov/omim/).Column 2 provides diseases associated with the cytologic band disclosedin Table 1B.1, as determined using the Morbid Map database. TABLE 5 OMIMReference Description 100710 Myasthenic syndrome, slow-channelcongenital, 601462 102200 Somatotrophinoma 102700 Severe combinedimmunodeficiency due to ADA deficiency 102700 Hemolytic anemia due toADA excess 102770 Myoadenylate deaminase deficiency 103050 Autism,succinylpurinemic 103050 Adenylosuccinase deficiency 103581 Albrighthereditary osteodystrophy-2 103600 [Dysalbuminemic hyperthyroxinemia]103600 [Dysalbuminemic hyperzincemia], 194470 103600 Analbuminemia103950 Emphysema due to alpha-2-macroglobulin deficiency 104150 [AFPdeficiency, congenital] 104150 [Hereditary persistence ofalpha-fetoprotein] 104500 Amelogenesis imperfecta-2, hypoplastic localtype 106100 Angioedema, hereditary 106150 Hypertension, essential,susceptibility to 106150 Preeclampsia, susceptibility to 106165Hypertension, essential, 145500 106180 Myocardial infarction,susceptibility to 107250 Anterior segment mesenchymal dysgenesis 107300Antithrombin III deficiency 107777 Diabetes insipidus, nephrogenic,autosomal recessive, 222000 108725 Atherosclerosis, susceptibility to108985 Atrophia areata 110100 Blepharophimosis, epicanthus inversus, andptosis, type 1 112410 Hypertension with brachydactyly 114240 Musculardystrophy, limb-girdle, type 2A, 253600 116806 Colorectal cancer 116860Cavernous angiomatous malformations 117700 [Hypoceruloplasminemia,hereditary] 117700 Hemosiderosis, systemic, due to aceruloplasminemia118210 Charcot-Marie-Tooth neuropathy-2A 120070 Alport syndrome,autosomal recessive, 203780 120120 Epidermolysis bullosa dystrophica,dominant, 131750 120120 Epidermolysis bullosa dystrophica, recessive,226600 120120 Epidermolysis bullosa, pretibial, 131850 120131 Alportsyndrome, autosomal recessive, 203780 120131 Hematuria, familial benign120140 Osteoarthrosis, precocious 120140 SED congenita 120140 SMEDStrudwick type 120140 Stickler syndrome, type I 120140 Wagner syndrome,type II 120140 Achondrogenesis-hypochondrogenesis, type II 120140 Kniestdysplasia 120260 Epiphyseal dysplasia, multiple, type 2, 600204 120436Muir-Torre family cancer syndrome, 158320 120436 Turcot syndrome withglioblastoma, 276300 120436 Colorectal cancer, hereditary nonpolyposis,type 2 120550 C1q deficiency, type A 120570 C1q deficiency, type B120575 C1q deficiency, type C 120700 C3 deficiency 121800 Cornealdystrophy, crystalline, Schnyder 123000 Craniometaphyseal dysplasia123620 Cataract, cerulean, type 2, 601547 123940 White sponge nevus,193900 124030 Parkinsonism, susceptibility to 124030 Debrisoquinesensitivity 125852 Insulin-dependent diabetes mellitus-2 126337 Myxoidliposarcoma 126451 Schizophrenia, susceptibility to 126452 Autonomicnervous system dysfunction 126452 [Novelty seeking personality] 126650Chloride diarrhea, congenital, Finnish type, 214700 126650 Colon cancer129900 EEC syndrome-1 130500 Elliptocytosis-1 130650 Beckwith-Wiedemannsyndrome 131100 Multiple endocrine neoplasia I 131100 Prolactinoma,hyperparathyroidism, carcinoid syndrome 131100 Carcinoid tumor of lung131210 Atherosclerosis, susceptibility to 133171 [Erythrocytosis,familial], 133100 133200 Erythrokeratodermia variabilis 133450Neuroepithelioma 133450 Ewing sarcoma 133780 Vitreoretinopathy,exudative, familial 134790 Hyperferritinemia-cataract syndrome, 600886134820 Dysfibrinogenemia, alpha type, causing bleeding diathesis 134820Dysfibrinogenemia, alpha type, causing recurrent thrombosis 134820Amyloidosis, hereditary renal, 105200 134830 Dysfibrinogenemia, betatype 134850 Dysfibrinogenemia, gamma type 134850 Hypofibrinogenemia,gamma type 135700 Fibrosis of extraocular muscles, congenital, 1 136132[Fish-odor syndrome], 602079 136836 Fucosyltransferase-6 deficiency138030 [Hyperproglucagonemia] 138140 Glucose transport defect,blood-brain barrier 138190 Diabetes mellitus, noninsulin-dependent138300 Hemolytic anemia due to glutathione reductase deficiency 138320Hemolytic anemia due to glutathione peroxidase deficiency 138700[Apolipoprotein H deficiency] 120436 Muir-Torre family cancer syndrome,158320 120436 Turcot syndrome with glioblastoma, 276300 120436Colorectal cancer, hereditary nonpolyposis, type 2 120550 C1qdeficiency, type A 120570 C1q deficiency, type B 120575 C1q deficiency,type C 120700 C3 deficiency 121800 Corneal dystrophy, crystalline,Schnyder 123000 Craniometaphyseal dysplasia 123620 Cataract, cerulean,type 2, 601547 123940 White sponge nevus, 193900 124030 Parkinsonism,susceptibility to 124030 Debrisoquine sensitivity 125852Insulin-dependent diabetes mellitus-2 126337 Myxoid liposarcoma 126451Schizophrenia, susceptibility to 126452 Autonomic nervous systemdysfunction 126452 [Novelty seeking personality] 126650 Chloridediarrhea, congenital, Finnish type, 214700 126650 Colon cancer 129900EEC syndrome-1 130500 Elliptocytosis-1 130650 Beckwith-Wiedemannsyndrome 131100 Multiple endocrine neoplasia I 131100 Prolactinoma,hyperparathyroidism, carcinoid syndrome 131100 Carcinoid tumor of lung131210 Atherosclerosis, susceptibility to 133171 [Erythrocytosis,familial], 133100 133200 Erythrokeratodermia variabilis 133450Neuroepithelioma 133450 Ewing sarcoma 133780 Vitreoretinopathy,exudative, familial 134790 Hyperferritinemia-cataract syndrome, 600886134820 Dysfibrinogenemia, alpha type, causing bleeding diathesis 134820Dysfibrinogenemia, alpha type, causing recurrent thrombosis 134820Amyloidosis, hereditary renal, 105200 134830 Dysfibrinogenemia, betatype 134850 Dysfibrinogenemia, gamma type 134850 Hypofibrinogenemia,gamma type 135700 Fibrosis of extraocular muscles, congenital, 1 136132[Fish-odor syndrome], 602079 136836 Fucosyltransferase-6 deficiency138030 [Hyperproglucagonemia] 138140 Glucose transport defect,blood-brain barrier 138190 Diabetes mellitus, noninsulin-dependent138300 Hemolytic anemia due to glutathione reductase deficiency 138320Hemolytic anemia due to glutathione peroxidase deficiency 138700[Apolipoprotein H deficiency] 138720 Bernard-Soulier syndrome, type B138981 Pulmonary alveolar proteinosis, 265120 139250 Isolated growthhormone deficiency, Illig type with absent GH and Kowarski type withbioinactive GH 139350 Epidermolytic hyperkeratosis, 113800 139350Keratoderma, palmoplantar, nonepidermolytic 141750Alpha-thalassemia/mental retardation syndrome, type 1 141800Methemoglobinemias, alpha- 141800 Thalassemias, alpha- 141800Erythremias, alpha- 141800 Heinz body anemias, alpha- 141850Thalassemia, alpha- 141850 Erythrocytosis 141850 Heinz body anemia141850 Hemoglobin H disease 141850 Hypochromic microcytic anemia 141900Methemoglobinemias, beta- 141900 Sickle cell anemia 141900 Thalassemias,beta- 141900 Erythremias, beta- 141900 HPFH, deletion type 141900 Heinzbody anemias, beta- 142000 Thalassemia due to Hb Lepore 142000Thalassemia, delta- 142200 HPFH, nondeletion type A 142250 HPFH,nondeletion type G 142270 Hereditary persistence of fetal hemoglobin143890 Hypercholesterolemia, familial 145001 Hyperparathyroidism-jawtumor syndrome 145260 Pseudohypoaldosteronism, type II 145410 Opitz Gsyndrome, type II 145981 Hypocalciuric hypercalcemia, type II 146150Hypomelanosis of Ito 147050 Atopy 147141 Leukemia, acute lymphoblastic147200 [Kappa light chain deficiency] 147545 Diabetes mellitus,noninsulin-dependent 147670 Rabson-Mendenhall syndrome 147670 Diabetesmellitus, insulin-resistant, with acanthosis nigricans 147670Leprechaunism 148040 Epidermolysis bullosa simplex, Koebner,Dowling-Meara, and Weber- Cockayne types, 131900, 131760, 131800 148041Pachyonychia congenita, Jadassohn-Lewandowsky type, 167200 148043Meesmann corneal dystrophy, 122100 148070 Liver disease, susceptibilityto, from hepatotoxins or viruses 148370 Keratolytic winter erythema150000 Exertional myoglobinuria due to deficiency of LDH-A 150200[Placental lactogen deficiency] 150210 Lactoferrin-deficientneutrophils, 245480 151410 Leukemia, chronic myeloid 151440 Leukemia,T-cell acute lymphoblastoid 152760 Hypogonadotropic hypogonadism due toGNRH deficiency, 227200 153454 Ehlers-Danlos syndrome, type VI, 225400153700 Macular dystrophy, vitelliform type 154275 Malignant hyperthermiasusceptibility 2 154276 Malignant hyperthermia susceptibility 3 156850Cataract, congenital, with microphthalmia 157147 Abetalipoproteinemia,200100 157640 PEO with mitochondrial DNA deletions, type 1 160781Cardiomyopathy, hypertrophic, mid-left ventricular chamber type 161015Mitochondrial complex I deficiency, 252010 162200 Neurofibromatosis,type 1 162200 Watson syndrome, 193520 164009 Leukemia, acutepromyelocytic, NUMA/RARA type 164731 Ovarian carcinoma, 167000 164790Colorectal cancer 164920 Piebaldism 164920 Mast cell leukemia 164920Mastocytosis with associated hematologic disorder 164953 Liposarcoma168360 Paraneoplastic sensory neuropathy 168461 Multiple myeloma, 254250168461 Parathyroid adenomatosis 1 168461 Centrocytic lymphoma 168468Metaphyseal chondrodysplasia, Murk Jansen type, 156400 168470 Humoralhypercalcemia of malignancy 169600 Hailey—Hailey disease 170650Periodontitis, juvenile 171760 Hypophosphatasia, adult, 146300 171760Hypophosphatasia, infantile, 241500 172400 Hemolytic anemia due toglucosephosphate isomerase deficiency 172400 Hydrops fetalis, one form173360 Thrombophilia due to excessive plasminogen activator inhibitor173360 Hemorrhagic diathesis due to PAI1 deficiency 173610 Plateletalpha/delta storage pool deficiency 173870 Xeroderma pigmentosum 173870Fanconi anemia 174900 Polyposis, juvenile intestinal 176100 Porphyriacutanea tarda 176100 Porphyria, hepatoerythropoietic 176730 Diabetesmellitus, rare form 176730 Hyperproinsulinemia, familial 176730 MODY,one form 176830 Obesity, adrenal insufficiency, and red hair 176830 ACTHdeficiency 176960 Pituitary tumor, invasive 178300 Ptosis, hereditarycongenital, 1 178640 Pulmonary alveolar proteinosis, congenital, 265120180100 Retinitis pigmentosa-1 180105 Retinitis pigmentosa-10 180380Night blindness, congenital stationery, rhodopsin-related 180380Retinitis pigmentosa, autosomal recessive 180380 Retinitis pigmentosa-4,autosomal dominant 180721 Retinitis pigmentosa, digenic 180840Susceptibility to IDDM 180901 Malignant hyperthermia susceptibility 1,145600 180901 Central core disease, 117000 181405 Scapuloperoneal spinalmuscular atrophy, New England type 181430 Scapuloperoneal syndrome,myopathic type 181600 Sclerotylosis 182138 Anxiety-related personalitytraits 182279 Prader-Willi syndrome 182280 Small-cell cancer of lung182380 Glucose/galactose malabsorption 182601 Spastic paraplegia-4185430 Atherosclerosis, susceptibility to 185470 Myopathy due tosuccinate dehydrogenase deficiency 186580 Arthrocutaneouvealgranulomatosis 186921 Leukemia, T-cell acute lymphoblastic 188070Bleeding disorder due to defective thromboxane A2 receptor 188450Goiter, adolescent multinodular 188450 Goiter, nonendemic, simple 188450Hypothyroidism, hereditary congenital 188826 Sorsby fundus dystrophy,136900 189800 Preeclampsia/eclampsia 190020 Bladder cancer, 109800190040 Meningioma, SIS-related 190040 Dermatofibrosarcoma protuberans190040 Giant-cell fibroblastoma 190900 Colorblindness, tritan 191044Cardiomyopathy, familial hypertrophic 191092 Tuberous sclerosis-2 191170Colorectal cancer, 114500 191170 Li-Fraumeni syndrome 191181 Cervicalcarcinoma 191290 Segawa syndrome, recessive 192340 Diabetes insipidus,neurohypophyseal, 125700 192500 Jervell and Lange-Nielsen syndrome,220400 192500 Long QT syndrome-1 193100 Hypophosphatemic rickets,autosomal dominant 193235 Vitreoretinopathy, neovascular inflammatory193400 von Willebrand disease 194071 Wilms tumor, type 2 194071Adrenocortical carcinoma, hereditary, 202300 200990 Acrocallosalsyndrome 203100 Waardenburg syndrome/ocular albinism, digenic, 103470203100 Albinism, oculocutaneous, type IA 203200 Albinism, ocular,autosomal recessive 203200 Albinism, oculocutaneous, type II 203500Alkaptonuria 203800 Alstrom syndrome 204500 Ceroid-lipofuscinosis,neuronal 2, classic late infantile 209901 Bardet-Biedl syndrome 1 212138Carnitine-acylcarnitine translocase deficiency 216900 Achromatopsia221770 Polycystic lipomembranous osteodysplasia with sclerosingleukencephalopathy 222800 Hemolytic anemia due to bisphosphoglyceratemutase deficiency 224120 Dyserythropoietic anemia, contenital, type I227220 [Eye color, brown] 227646 Fanconi anemia, type D 229800[Fructosuria] 230000 Fucosidosis 230350 Galactose epimerase deficiency231550 Achalasia-addisonianism-alacrimia syndrome 231670Glutaricaciduria, type I 231950 Glutathioninuria 232050Propionicacidemia, type II or pccB type 232600 McArdle disease 233700Chronic granulomatous disease due to deficiency of NCF-1 234200Neurodegeneration with brain iron accumulation 236730 Urofacial syndrome238600 Chylomicronemia syndrome, familial 238600 Combined hyperlipemia,familial 238600 Hyperlipoproteinemia I 238600 Lipoprotein lipasedeficiency 239100 Van Buchem disease 239500 Hyperprolinemia, type I240400 Scurvy 245000 Papillon-Lefevre syndrome 246450 HMG-CoA lyasedeficiency 246900 Lipoamide dehydrogenase deficiency 248510Mannosidosis, beta- 248600 Maple syrup urine disease, type Ia 248611Maple syrup urine disease, type Ib 249000 Meckel syndrome 249270Thiamine-responsive megaloblastic anemia 253250 Mulibrey nanism 254210Myasthenia gravis, familial infantile 255800 Schwartz-Jampel syndrome256700 Neuroblastoma 257200 Niemann-Pick disease, type A 257200Niemann-Pick disease, type B 259700 Osteopetrosis, recessive 259770Osteoporosis-pseudoglioma syndrome 259900 Hyperoxaluria, primary, type 1261510 Pseudo-Zellweger syndrome 262000 Bjornstad syndrome 266150Pyruvate carboxylase deficiency 266300 [Hair color, red] 271900 Canavandisease 274180 Thromboxane synthase deficiency 275350 Transcobalamin IIdeficiency 276901 Usher syndrome, type 2 276902 Usher syndrome, type 3276903 Usher syndrome, type 1B 276903 Deafness, autosomal dominant 11,neurosensory, 601317 276903 Deafness, autosomal recessive 2,neurosensory, 600060 300046 Mental retardation, X-linked 23, nonspecific300088 Epilepsy, female restricted, with mental retardation 300123Mental retardation with isolated growth hormone deficiency 300300 XLAand isolated growth hormone deficiency, 307200 300300Agammaglobulinemia, type 1, X-linked 301201 Amelogenesis imperfecta-3,hypoplastic type 301500 Fabry disease 301590 Anophthalmos-1 301835 Artssyndrome 301845 Bazex syndrome 301900 Borjeson-Forssman-Lehmann syndrome303400 Cleft palate, X-linked 303630 Alport syndrome, 301050 303630Leiomyomatosis-nephropathy syndrome, 308940 303631 Leiomyomatosis,diffuse, with Alport syndrome 304340 Mental retardation, X-linked,syndromic-5, with Dandy-Walker malformation, basal ganglia disease, andseizures 304500 Deafness, X-linked 2, perceptive congenital 304700Mohr-Tranebjaerg syndrome 304700 Deafness, X-linked 1, progressive304700 Jensen syndrome, 311150 305450 FG syndrome 306900 Hemophilia B307150 Hypertrichosis, congenital generalized 307700 Hypoparathyroidism,X-linked 308000 HPRT-related gout 308000 Lesch-Nyhan syndrome 309000Lowe syndrome 309300 Megalocornea, X-linked 309605 Mental retardation,X-linked, syndromic-4, with congenital contractures and low fingertiparches 310490 Cowchock syndrome 311850 Phosphoribosyl pyrophosphatesynthetase-related gout 312080 Pelizaeus-Merzbacher disease 312080Spastic paraplegia-2, 312920 313850 Thoracoabdominal syndrome 600040Colorectal cancer 600045 Xeroderma pigmentosum, group E, subtype 2600079 Colon cancer 600138 Retinitis pigmentosa-11 600140Rubenstein-Taybi syndrome, 180849 600143 Epilepsy, progressive, withmental retardation 600163 Long QT syndrome-3 600179 Leber congenitalamaurosis, type I, 204000 600194 Ichthyosis bullosa of Siemens, 146800600231 Palmoplantar keratoderma, Bothnia type 600273 Polycystic kidneydisease, infantile severe, with tuberous sclerosis 600276 Cerebralarteriopathy with subcortical infarcts and leukoencephalopathy, 125310600319 Diabetes mellitus, insulin-dependent, 4 600332 Rippling muscledisease-1 600512 Epilepsy, partial 600528 CPT deficiency, hepatic, typeI, 255120 600536 Myopathy, congenital 600698 Salivary adenoma 600698Uterine leiomyoma 600698 Lipoma 600698 Lipomatosis, mutiple, 151900600759 Alzheimer disease-4 600808 Enuresis, nocturnal, 2 600839 Barttersyndrome, 241200 600850 Schizophrenia disorder-4 600856Beckwith-Wiedemann syndrome, 130650 600881 Cataract, congenital,zonular, with sutural opacities 600882 Charcot-Marie-Tooth neuropathy-2B600900 Muscular dystrophy, limb-girdle, type 2E 600918 Cystinuria, typeIII 600956 Persistent Mullerian duct syndrome, type II, 261550 600957Persistent Mullerian duct syndrome, type I, 261550 600977 Conedystrophy, progressive 600983 Pseudohypoaldosteronism type I, autosomaldominant, 177735 600996 Arrhythmogenic right ventricular dysplasia-2601154 Cardiomyopathy, dilated, 1E 601199 Neonatal hyperparathyroidism,239200 601199 Hypocalcemia, autosomal dominant, 601198 601199Hypocalciuric hypercalcemia, type I, 145980 601202 Cataract, anteriorpolar-2 601238 Cerebellar ataxia, Cayman type 601284 Hereditaryhemorrhagic telangiectasia-2, 600376 601313 Polycystic kidney disease,adult type I, 173900 601385 Prostate cancer 601414 Retinitispigmentosa-18 601458 Inflammatory bowel disease-2 601471 Moebiussyndrome-2 601623 Angelman syndrome 601652 Glaucoma 1A, primary openangle, juvenile-onset, 137750 601669 Hirschsprung disease, one form601680 Distal arthrogryposis, type 2B 601682 Glaucoma 1C, primary openangle 601691 Retinitis pigmentosa-19, 601718 601691 Stargardt disease-1,248200 601691 Cone-rod dystrophy 3 601691 Fundus flavimaculatus withmacular dystrophy, 248200 601718 Retinitis pigmentosa-19 601744 Systemiclupus erythematosus, susceptibility to, 1 601769 Osteoporosis,involutional 601769 Rickets, vitamin D-resistant, 277440 601777 Conedystrophy, progressive 601785 Carbohydrate-deficient glycoproteinsyndrome, type I, 212065 601800 [Hair color, brown] 601843Hypothyroidism, congenital, 274400 601846 Muscular dystrophy with rimmedvacuoles 601884 [High bone mass] 601889 Lymphoma, diffuse large cell601928 Monilethrix, 158000 601954 Muscular dystrophy, limb-girdle, type2G 601975 Ectodermal dysplasia/skin fragility syndrome 602025Obesity/hyperinsulinism, susceptibility to 602092 Deafness, autosomalrecessive 18 602094 Lipodystrophy, familial partial 602099 Amytrophiclateral sclerosis-5 602116 Glioma 602117 Prader-Willi syndrome 602134Tremor, familial essential, 2 602136 Refsum disease, infantile, 266510602136 Zellweger syndrome-1, 214100 602136 Adrenoleukodystrophy,neonatal, 202370 602153 Monilethrix, 158000 602216 Peutz-Jegherssyndrome, 175200 602403 Alzheimer disease, susceptibility to 602447Coronary artery disease, susceptibility to 602477 Febrile convulsions,familial, 2 602568 Homocystinuria-megaloblastic anemia, cbl E type,236270 602574 Deafness, autosomal dominant 12, 601842 602574 Deafness,autosomal dominant 8, 601543 602629 Dystonia-6, torsion 602631Rhabdomyosarcoma, 268210 602631 Breast Cancer 602716 Nephrosis-1,congenital, Finnish type, 256300 602771 Muscular dystrophy, congenital,with early spine rigidity 601744 Systemic lupus erythematosus,susceptibility to, 1 601769 Osteoporosis, involutional 601769 Rickets,vitamin D-resistant, 277440 601777 Cone dystrophy, progressive 601785Carbohydrate-deficient glycoprotein syndrome, type I, 212065 601800[Hair color, brown] 601843 Hypothyroidism, congenital, 274400 601846Muscular dystrophy with rimmed vacuoles 601884 [High bone mass] 601889Lymphoma, diffuse large cell 601928 Monilethrix, 158000 601954 Musculardystrophy, limb-girdle, type 2G 601975 Ectodermal dysplasia/skinfragility syndrome 602025 Obesity/hyperinsulinism, susceptibility to602092 Deafness, autosomal recessive 18 602094 Lipodystrophy, familialpartial 602099 Amytrophic lateral sclerosis-5 602116 Glioma 602117Prader-Willi syndrome 602134 Tremor, familial essential, 2 602136 Refsumdisease, infantile, 266510 602136 Zellweger syndrome-1, 214100 602136Adrenoleukodystrophy, neonatal, 202370 602153 Monilethrix, 158000 602216Peutz-Jeghers syndrome, 175200 602403 Alzheimer disease, susceptibilityto 602447 Coronary artery disease, susceptibility to 602477 Febrileconvulsions, familial, 2 602568 Homocystinuria-megaloblastic anemia, cblE type, 236270 602574 Deafness, autosomal dominant 12, 601842 602574Deafness, autosomal dominant 8, 601543 602629 Dystonia-6, torsion 602631Rhabdomyosarcoma, 268210 602631 Breast Cancer 602716 Nephrosis-1,congenital, Finnish type, 256300 602771 Muscular dystrophy, congenital,with early spine rigidityMature Polypeptides

The present invention also encompasses mature forms of a polypeptidehaving the amino acid sequence of SEQ ID NO:Y and/or the amino acidsequence encoded by the cDNA in a deposited clone. Polynucleotidesencoding the mature forms (such as, for example, the polynucleotidesequence in SEQ ID NO:X and/or the polynucleotide sequence contained inthe cDNA of a deposited clone) are also encompassed by the invention.Moreover, fragments or varients of these polypeptides (such as,fragments as described herein, polypeptides at least 80%, 85%, 90%, 95%,96%, 97%, 98%, 99%, or 100% identical to these polypeptides, orpolypeptides encoded by a polynucleotide that hybridizes under stringentconditions to the complementary strand of the polynucleotide encodingthese polypeptides) are also encompassed by the invention. In preferredembodiments, these fragments or variants retain one or more functionalacitivities of the full-length or mature form of the polypeptide (e.g.,biological activity (such as, for example, activity useful in detecting,preventing, diagnosing, prognosticating, treating, and/or amelioratingcardiovascular disorders), antigenicity (ability to bind, or competewith a polypeptide of the invention for binding, to an anti-polypeptideof the invention antibody), immunogenicity (ability to generate antibodywhich binds to a specific polypeptide of the invention), ability to formmultimers with polypeptides of the invention, and ability to bind to areceptor or ligand for a polypeptide of the invention). Antibodies thatbind the polypeptides of the invention, and polynucleotides encodingthese polypeptides are also encompassed by the invention.

According to the signal hypothesis, proteins secreted by mammalian cellshave a signal or secretary leader sequence which is cleaved from themature protein once export of the growing protein chain across the roughendoplasmic reticulum has been initiated. Most mammalian cells and eveninsect cells cleave secreted proteins with the same specificity.However, in some cases, cleavage of a secreted protein is not entirelyuniform, which results in two or more mature species of the protein.Further, it has long been known that cleavage specificity of a secretedprotein is ultimately determined by the primary structure of thecomplete protein, that is, it is inherent in the amino acid sequence ofthe polypeptide.

Methods for predicting whether a protein has a signal sequence, as wellas the cleavage point for that sequence, are available. For instance,the method of McGeoch, Virus Res. 3:271-286 (1985), uses the informationfrom a short N-terminal charged region and a subsequent uncharged regionof the complete (uncleaved) protein. The method of von Heinje, NucleicAcids Res. 14:46834690 (1986) uses the information from the residuessurrounding the cleavage site, typically residues −13 to +2, where +1indicates the amino terminus of the secreted protein. The accuracy ofpredicting the cleavage points of known mammalian secretory proteins foreach of these methods is in the range of 75-80%. (von Heinje, supra.)However, the two methods do not always produce the same predictedcleavage point(s) for a given protein.

In the present case, the deduced amino acid sequence of the secretedpolypeptide was analyzed by a computer program called SignalP (HenrikNielsen et al., Protein Engineering 10: 1-6 (1997)), which predicts thecellular location of a protein based on the amino acid sequence. As partof this computational prediction of localization, the methods of McGeochand von Heinje are incorporated. The analysis of the amino acidsequences of the secreted proteins described herein by this programprovided the results shown in Table 1A.

In specific embodiments, polypeptides of the invention comprise, oralternatively consist of, the predicted mature form of the polypeptideas delineated in columns 14 and 15 of Table 1A. Moreover, fragments orvariants of these polypeptides (such as, fragments as described herein,polypeptides at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100%identical to these polypeptides, or polypeptides encoded by apolynucleotide that hybridizes under stringent conditions to thecomplementary strand of the polynucleotide encoding these polypeptides)are also encompassed by the invention. In preferred embodiments, thesefragments or variants retain one or more functional acitivities of thefull-length or mature form of the polypeptide (e.g., biological activity(such as, for example, activity useful in detecting, preventing,diagnosing, prognosticating, treating, and/or amelioratingcardiovascular disorders), antigenicity (ability to bind, or competewith a polypeptide of the invention for binding, to an anti-polypeptideof the invention antibody), immunogenicity (ability to generate antibodywhich binds to a specific polypeptide of the invention), ability to formmultimers with polypeptides of the invention, and ability to bind to areceptor or ligand for a polypeptide of the invention). Antibodies thatbind the polypeptides of the invention, and polynucleotides encodingthese polypeptides are also encompassed by the invention.

Polynucleotides encoding proteins comprising, or consisting of, thepredicted mature form of polypeptides of the invention (e.g.,polynucleotides having the sequence of SEQ ID NO: X (Table 1A, column4), the sequence delineated in columns 7 and 8 of Table 1A, and asequence encoding the mature polypeptide delineated in columns 14 and 15of Table 1A (e.g., the sequence of SEQ ID NO:X encoding the maturepolypeptide delineated in columns 14 and 15 of Table 1)) are alsoencompassed by the invention, as are fragments or variants of thesepolynucleotides (such as, fragments as described herein, polynucleotidesat least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical tothese polynucleotides, and nucleic acids which hybridizes understringent conditions to the complementary strand of the polynucleotide).

As one of ordinary skill would appreciate, however, cleavage sitessometimes vary from organism to organism and cannot be predicted withabsolute certainty. Accordingly, the present invention provides secretedpolypeptides having a sequence shown in SEQ ID NO:Y which have anN-terminus beginning within 15 residues of the predicted cleavage point(i.e., having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 moreor less contiguous residues of SEQ ID NO:Y at the N-terminus whencompared to the predicted mature form of the polypeptide (e.g., themature polypeptide delineated in columns 14 and 15 of Table 1).Similarly, it is also recognized that in some cases, cleavage of thesignal sequence from a secreted protein is not entirely uniform,resulting in more than one secreted species. These polypeptides, and thepolynucleotides encoding such polypeptides, are contemplated by thepresent invention.

Moreover, the signal sequence identified by the above analysis may notnecessarily predict the naturally occurring signal sequence. Forexample, the naturally occurring signal sequence may be further upstreamfrom the predicted signal sequence. However, it is likely that thepredicted signal sequence will be capable of directing the secretedprotein to the ER. Nonetheless, the present invention provides themature protein produced by expression of the polynucleotide sequence ofSEQ ID NO:X and/or the polynucleotide sequence contained in the cDNA ofa deposited clone, in a mammalian cell (e.g., COS cells, as describedbelow). These polypeptides, and the polynucleotides encoding suchpolypeptides, are contemplated by the present invention.

Polynucleotide and Polypeptide Variants

The present invention is also directed to variants of the polynucleotidesequence disclosed in SEQ ID NO:X or the complementary strand thereto,nucleotide sequences encoding the polypeptide of SEQ ID NO:Y, thenucleotide sequence of SEQ ID NO:X that encodes the polypeptide sequenceas defined in columns 13 and 14 of Table 1A, nucleotide sequencesencoding the polypeptide sequence as defined in columns 13 and 14 ofTable 1A, the nucleotide sequence of SEQ ID NO:X encoding thepolypeptide sequence as defined in column 7 of Table 1B.1, nucleotidesequences encoding the polypeptide as defined in Table 1B.1, thenucleotide sequence as defined in columns 8 and 9 of Table 2, nucleotidesequences encoding the polypeptide encoded by the nucleotide sequence asdefined in columns 8 and 9 of Table 2, the nucleotide sequence asdefined in column 6 of Table 1C, nucleotide sequences encoding thepolypeptide encoded by the nucleotide sequence as defined in column 6 ofTable 1C, the cDNA sequence contained in ATCC Deposit No:Z, nucleotidesequences encoding the polypeptide encoded by the cDNA sequencecontained in ATCC Deposit No:Z, and/or nucleotide sequences encoding amature (secreted) polypeptide encoded by the cDNA sequence contained inATCC Deposit No:Z.

The present invention also encompasses variants of the polypeptidesequence disclosed in SEQ ID NO:Y, the polypeptide as defined in columns13 and 14 of Table 1A, the polypeptide sequence as defined in Table1B.1, a polypeptide sequence encoded by the polynucleotide sequence inSEQ ID NO:X, a polypeptide sequence encoded by the nucleotide sequenceas defined in columns 8 and 9 of Table 2, a polypeptide sequence encodedby the nucleotide sequence as defined in column 6 of Table 1C, apolypeptide sequence encoded by the complement of the polynucleotidesequence in SEQ ID NO:X, the polypeptide sequence encoded by the cDNAsequence contained in ATCC Deposit No:Z and/or a mature (secreted)polypeptide encoded by the cDNA sequence contained in ATCC Deposit No:Z.

“Variant” refers to a polynucleotide or polypeptide differing from thepolynucleotide or polypeptide, of the present invention, but retainingessential properties thereof. Generally, variants are overall closelysimilar, and, in many regions, identical to the polynucleotide orpolypeptide of the present invention.

Thus, one aspect of the invention provides an isolated nucleic acidmolecule comprising, or alternatively consisting of, a polynucleotidehaving a nucleotide sequence selected from the group consisting of: (a)a nucleotide sequence described in SEQ ID NO:X or contained in the cDNAsequence of ATCC Deposit No:Z; (b) a nucleotide sequence in SEQ ID NO:Xor the cDNA in ATCC Deposit No:Z which encodes the complete amino acidsequence of SEQ ID NO:Y or the complete amino acid sequence encoded bythe cDNA in ATCC Deposit No:Z; (c) a nucleotide sequence in SEQ ID NO:Xor the cDNA in ATCC Deposit No:Z which encodes a mature polypeptide(i.e., a secreted polypeptide (e.g., as delineated in columns 14 and 15of Table 1A)); (d) a nucleotide sequence in SEQ ID NO:X or the cDNAsequence of ATCC Deposit No:Z, which encodes a biologically activefragment of a polypeptide; (e) a nucleotide sequence in SEQ ID NO:X orthe cDNA sequence of ATCC Deposit No:Z, which encodes an antigenicfragment of a polypeptide; (f) a nucleotide sequence encoding apolypeptide comprising the complete amino acid sequence of SEQ ID NO:Yor the complete amino acid sequence encoded by the cDNA in ATCC DepositNo:Z; (g) a nucleotide sequence encoding a mature polypeptide of theamino acid sequence of SEQ ID NO:Y (i.e., a secreted polypeptide (e.g.,as delineated in columns 14 and 15 of Table 1A)) or a mature polypeptideof the amino acid sequence encoded by the cDNA in ATCC Deposit No:Z; (h)a nucleotide sequence encoding a biologically active fragment of apolypeptide having the complete amino acid sequence of SEQ ID NO:Y orthe complete amino acid sequence encoded by the cDNA in ATCC DepositNo:Z; (i) a nucleotide sequence encoding an antigenic fragment of apolypeptide having the complete amino acid sequence of SEQ ID NO:Y orthe complete amino acid sequence encoded by the cDNA in ATCC DepositNo:Z; and (O) a nucleotide sequence complementary to any of thenucleotide sequences in (a), (b), (c), (d), (e), (f), (g), (h), or (i)above.

The present invention is also directed to nucleic acid molecules whichcomprise, or alternatively consist of, a nucleotide sequence which is atleast 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%, identical to, forexample, any of the nucleotide sequences in (a), (b), (c), (d), (e),(f), (g), (h), (i), or (j) above, the nucleotide coding sequence in SEQID NO:X or the complementary strand thereto, the nucleotide codingsequence of the cDNA contained in ATCC Deposit No:Z or the complementarystrand thereto, a nucleotide sequence encoding the polypeptide of SEQ IDNO:Y, a nucleotide sequence encoding a polypeptide sequence encoded bythe nucleotide sequence in SEQ ID NO:X, a polypeptide sequence encodedby the complement of the polynucleotide sequence in SEQ ID NO:X, anucleotide sequence encoding the polypeptide encoded by the cDNAcontained in ATCC Deposit No:Z, the nucleotide coding sequence in SEQ IDNO:X as defined in columns 8 and 9 of Table 2 or the complementarystrand thereto, a nucleotide sequence encoding the polypeptide encodedby the nucleotide sequence in SEQ ID NO:X as defined in columns 8 and 9of Table 2 or the complementary strand thereto, the nucleotide codingsequence in SEQ ID NO:B as defined in column 6 of Table 1C or thecomplementary strand thereto, a nucleotide sequence encoding thepolypeptide encoded by the nucleotide sequence in SEQ ID NO:B as definedin column 6 of Table 1C or the complementary strand thereto, thenucleotide sequence in SEQ ID NO:X encoding the polypeptide sequence asdefined in Table 1B.1 or the complementary strand thereto, nucleotidesequences encoding the polypeptide as defined in Table 1B.1 or thecomplementary strand thereto, and/or polynucleotide fragments of any ofthese nucleic acid molecules (e.g., those fragments described herein).Polynucleotides which hybridize to the complement of these nucleic acidmolecules under stringent hybridization conditions or alternatively,under lower stringency conditions, are also encompassed by theinvention, as are polypeptides encoded by these polynucleotides andnucleic acids.

In a preferred embodiment, the invention encompasses nucleic acidmolecules which comprise, or alternatively, consist of a polynucleotidewhich hybridizes under stringent hybridization conditions, oralternatively, under lower stringency conditions, to a polynucleotide in(a), (b), (c), (d), (e), (f), (g), (h), or (i), above, as arepolypeptides encoded by these polynucleotides. In another preferredembodiment, polynucleotides which hybridize to the complement of thesenucleic acid molecules under stringent hybridization conditions, oralternatively, under lower stringency conditions, are also encompassedby the invention, as are polypeptides encoded by these polynucleotides.

In another embodiment, the invention provides a purified proteincomprising, or alternatively consisting of, a polypeptide having anamino acid sequence selected from the group consisting of: (a) thecomplete amino acid sequence of SEQ ID NO:Y or the complete amino acidsequence encoded by the cDNA in ATCC Deposit No:Z; (b) the amino acidsequence of a mature (secreted) form of a polypeptide having the aminoacid sequence of SEQ ID NO:Y (e.g., as delineated in columns 14 and 15of Table 1A) or a mature form of the amino acid sequence encoded by thecDNA in ATCC Deposit No:Z mature; (c) the amino acid sequence of abiologically active fragment of a polypeptide having the complete aminoacid sequence of SEQ ID NO:Y or the complete amino acid sequence encodedby the cDNA in ATCC Deposit No:Z; and (d) the amino acid sequence of anantigenic fragment of a polypeptide having the complete amino acidsequence of SEQ ID NO:Y or the complete amino acid sequence encoded bythe cDNA in ATCC Deposit No:Z.

The present invention is also directed to proteins which comprise, oralternatively consist of, an amino acid sequence which is at least 80%,85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%, identical to, for example,any of the amino acid sequences in (a), (b), (c), or (d), above, theamino acid sequence shown in SEQ ID NO:Y, the amino acid sequenceencoded by the cDNA contained in ATCC Deposit No:Z, the amino acidsequence of the polypeptide encoded by the nucleotide sequence in SEQ IDNO:X as defined in columns 8 and 9 of Table 2, the amino acid sequenceof the polypeptide encoded by the nucleotide sequence in SEQ ID NO:B asdefined in column 6 of Table 1C, the amino acid sequence as defined inTable 1B.1, an amino acid sequence encoded by the nucleotide sequence inSEQ ID NO:X, and an amino acid sequence encoded by the complement of thepolynucleotide sequence in SEQ ID NO:X. Fragments of these polypeptidesare also provided (e.g., those fragments described herein). Furtherproteins encoded by polynucleotides which hybridize to the complement ofthe nucleic acid molecules encoding these amino acid sequences understringent hybridization conditions or alternatively, under lowerstringency conditions, are also encompassed by the invention, as are thepolynucleotides encoding these proteins.

By a nucleic acid having a nucleotide sequence at least, for example,95% “identical” to a reference nucleotide sequence of the presentinvention, it is intended that the nucleotide sequence of the nucleicacid is identical to the reference sequence except that the nucleotidesequence may include up to five point mutations per each 100 nucleotidesof the reference nucleotide sequence encoding the polypeptide. In otherwords, to obtain a nucleic acid having a nucleotide sequence at least95% identical to a reference nucleotide sequence, up to 5% of thenucleotides in the reference sequence may be deleted or substituted withanother nucleotide, or a number of nucleotides up to 5% of the totalnucleotides in the reference sequence may be inserted into the referencesequence. The query sequence may be an entire sequence referred to inTable 1B. 1 or Table 2 as the ORF (open reading frame), or any fragmentspecified as described herein.

As a practical matter, whether any particular nucleic acid molecule orpolypeptide is at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%identical to a nucleotide sequence of the present invention can bedetermined conventionally using known computer programs. A preferredmethod for determining the best overall match between a query sequence(a sequence of the present invention) and a subject sequence, alsoreferred to as a global sequence alignment, can be determined using theFASTDB computer program based on the algorithm of Brutlag et al. (Comp.App. Biosci. 6:237-245 (1990)). In a sequence alignment the query andsubject sequences are both DNA sequences. An RNA sequence can becompared by converting U's to T's. The result of said global sequencealignment is expressed as percent identity. Preferred parameters used ina FASTDB alignment of DNA sequences to calculate percent identity are:Matdix=Unitary, k-tuple=4, Mismatch Penalty=1, Joining Penalty=30,Randomization Group Length=0, Cutoff Score=1, Gap Penalty=5, Gap SizePenalty 0.05, Window Size=500 or the length of the subject nucleotidesequence, whichever is shorter.

If the subject sequence is shorter than the query sequence because of 5′or 3′ deletions, not because of internal deletions, a manual correctionmust be made to the results. This is because the FASTDB program does notaccount for 5′ and 3′ truncations of the subject sequence whencalculating percent identity. For subject sequences truncated at the 5′or 3′ ends, relative to the query sequence, the percent identity iscorrected by calculating the number of bases of the query sequence thatare 5′ and 3′ of the subject sequence, which are not matched/aligned, asa percent of the total bases of the query sequence. Whether a nucleotideis matched/aligned is determined by results of the FASTDB sequencealignment. This percentage is then subtracted from the percent identity,calculated by the above FASTDB program using the specified parameters,to arrive at a final percent identity score. This corrected score iswhat is used for the purposes of the present invention. Only basesoutside the 5′ and 3′ bases of the subject sequence, as displayed by theFASTDB alignment, which are not matched/aligned with the query sequence,are calculated for the purposes of manually adjusting the percentidentity score.

For example, a 90 base subject sequence is aligned to a 100 base querysequence to determine percent identity. The deletions occur at the 5′end of the subject sequence and therefore, the FASTDB alignment does notshow a matched/alignment of the first 10 bases at 5′ end. The 10unpaired bases represent 10% of the sequence (number of bases at the 5′and 3′ ends not matched/total number of bases in the query sequence) so10% is subtracted from the percent identity score calculated by theFASTDB program. If the remaining 90 bases were perfectly matched thefinal percent identity would be 90%. In another example, a 90 basesubject sequence is compared with a 100 base query sequence. This timethe deletions are internal deletions so that there are no bases on the5′ or 3′ of the subject sequence which are not matched/aligned with thequery. In this case the percent identity calculated by FASTDB is notmanually corrected. Once again, only bases 5′ and 3′ of the subjectsequence which are not matched/aligned with the query sequence aremanually corrected for. No other manual corrections are to be made forthe purposes of the present invention.

By a polypeptide having an amino acid sequence at least, for example,95% “identical” to a query amino acid sequence of the present invention,it is intended that the amino acid sequence of the subject polypeptideis identical to the query sequence except that the subject, polypeptidesequence may include up to five amino acid alterations per each 100amino acids of the query amino acid sequence. In other words, to obtaina polypeptide having an amino acid sequence at least 95% identical to aquery amino acid sequence, up to 5% of the amino acid residues in thesubject sequence may be inserted, deleted, (indels) or substituted withanother amino acid. These alterations of the reference sequence mayoccur at the amino or carboxy terminal positions of the reference aminoacid sequence or anywhere between those terminal positions, interspersedeither individually among residues in the reference sequence or in oneor more contiguous groups within the reference sequence.

As a practical matter, whether any particular polypeptide is at least80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to, for instance, theamino acid sequence of a polypeptide referred to in Table 1A (e.g., theamino acid sequence delineated in columns 14 and 15) or a fragmentthereof, Table 1B (e.g., the amino acid sequence identified in column 6)or a fragment thereof, Table 2 (e.g., the amino acid sequence of thepolypeptide encoded by the polynucleotide sequence defined in columns 8and 9 of Table 2) or a fragment thereof, the amino acid sequence of thepolypeptide encoded by the polynucleotide sequence in SEQ ID NO:B asdefined in column 6 of Table 1C or a fragment thereof, the amino acidsequence of the polypeptide encoded by the nucleotide sequence in SEQ IDNO:X or a fragment thereof, or the amino acid sequence of thepolypeptide encoded by cDNA contained in ATCC Deposit No:Z, or afragment thereof, the amino acid sequence of a mature (secreted)polypeptide encoded by cDNA contained in ATCC Deposit No:Z, or afragment thereof, can be determined conventionally using known computerprograms. A preferred method for determining the best overall matchbetween a query sequence (a sequence of the present invention) and asubject sequence, also referred to as a global sequence alignment, canbe determined using the FASTDB computer program based on the algorithmof Brutlag et al. (Comp. App. Biosci.6:237-245 (1990)). In a sequencealignment the query and subject sequences are either both nucleotidesequences or both amino acid sequences. The result of said globalsequence alignment is expressed as percent identity. Preferredparameters used in a FASTDB amino acid alignment are: Matrix=PAM 0,k-tuple=2, Mismatch Penalty=1, Joining Penalty=20, Randomization GroupLength=0, Cutoff Score=1, Window Size=sequence length, Gap Penalty=5,Gap Size Penalty=0.05, Window Size=500 or the length of the subjectamino acid sequence, whichever is shorter.

If the subject sequence is shorter than the query sequence due to N- orC-terminal deletions, not because of internal deletions, a manualcorrection must be made to the results. This is because the FASTDBprogram does not account for N- and C-terminal truncations of thesubject sequence when calculating global percent identity. For subjectsequences truncated at the N- and C-termini, relative to the querysequence, the percent identity is corrected by calculating the number ofresidues of the query sequence that are N- and C-terminal of the subjectsequence, which are not matched/aligned with a corresponding subjectresidue, as a percent of the total bases of the query sequence. Whethera residue is matched/aligned is determined by results of the FASTDBsequence alignment. This percentage is then subtracted from the percentidentity, calculated by the above FASTDB program using the specifiedparameters, to arrive at a final percent identity score. This finalpercent identity score is what is used for the purposes of the presentinvention. Only residues to the N- and C-termini of the subjectsequence, which are not matched/aligned with the query sequence, areconsidered for the purposes of manually adjusting the percent identityscore. That is, only query residue positions outside the farthest N- andC-terminal residues of the subject sequence.

For example, a 90 amino acid residue subject sequence is aligned with a100 residue query sequence to determine percent identity. The deletionoccurs at the N-terminus of the subject sequence and therefore, theFASTDB alignment does not show a matching/alignment of the first 10residues at the N-terminus. The 10 unpaired residues represent 10% ofthe sequence (number of residues at the N- and C-termini notmatched/total number of residues in the query sequence) so 10% issubtracted from the percent identity score calculated by the FASTDBprogram. If the remaining 90 residues were perfectly matched the finalpercent identity would be 90%. In another example, a 90 residue subjectsequence is compared with a 100 residue query sequence. This time thedeletions are internal deletions so there are no residues at the N- orC-termini of the subject sequence which are not matched/aligned with thequery. In this case the percent identity calculated by FASTDB is notmanually corrected. Once again, only residue positions outside the N-and C-terminal ends of the subject sequence, as displayed in the FASTDBalignment, which are not matched/aligned with the query sequnce aremanually corrected for. No other manual corrections are to made for thepurposes of the present invention.

The polynucleotide variants of the invention may contain alterations inthe coding regions, non-coding regions, or both. Especially preferredare polynucleotide variants containing alterations which produce silentsubstitutions, additions, or deletions, but do not alter the propertiesor activities of the encoded polypeptide. Nucleotide variants producedby silent substitutions due to the degeneracy of the genetic code arepreferred. Moreover, polypeptide variants in which less than 50, lessthan 40, less than 30, less than 20, less than 10, or 5-50, 5-25, 5-10,1-5, or 1-2 amino acids are substituted, deleted, or added in anycombination are also preferred. Polynucleotide variants can be producedfor a variety of reasons, e.g., to optimize codon expression for aparticular host (change codons in the human mRNA to those preferred by abacterial host such as E. coli).

Naturally occurring variants are called “allelic variants,” and refer toone of several alternate forms of a gene occupying a given locus on achromosome of an organism. (Genes II, Lewin, B., ed., John Wiley & Sons,New York (1985)). These allelic variants can vary at either thepolynucleotide and/or polypeptide level and are included in the presentinvention. Alternatively, non-naturally occurring variants may beproduced by mutagenesis techniques or by direct synthesis.

Using known methods of protein engineering and recombinant DNAtechnology, variants may be generated to improve or alter thecharacteristics of the polypeptides of the present invention. Forinstance, one or more amino acids can be deleted from the N-terminus orC-terminus of the polypeptide of the present invention withoutsubstantial loss of biological function. As an example, Ron et al. (J.Biol. Chen. 268: 2984-2988 (1993)) reported variant KGF proteins havingheparin binding activity even after deleting 3, 8, or 27 amino-terminalamino acid residues. Similarly, Interferon gamma exhibited up to tentimes higher activity after deleting 8-10 amino acid residues from thecarboxy terminus of this protein. (Dobeli et al., J. Biotechnology7:199-216 (1988).)

Moreover, ample evidence demonstrates that variants often retain abiological activity similar to that of the naturally occurring protein.For example, Gayle and coworkers (J. Biol. Chem. 268:22105-22111 (1993))conducted extensive mutational analysis of human cytokine IL-la. Theyused random mutagenesis to generate over 3,500 individual IL-1a mutantsthat averaged 2.5 amino acid changes per variant over the entire lengthof the molecule. Multiple mutations were examined at every possibleamino acid position. The investigators found that “[m]ost of themolecule could be altered with little effect on either [binding orbiological activity].” In fact, only 23 unique amino acid sequences, outof more than 3,500 nucleotide sequences examined, produced a proteinthat significantly differed in activity from wild-type.

Furthermore, even if deleting one or more amino acids from theN-terminus or C-terminus of a polypeptide results in modification orloss of one or more biological functions, other biological activitiesmay still be retained. For example, the ability of a deletion variant toinduce and/or to bind antibodies which recognize the secreted form willlikely be retained when less than the majority of the residues of thesecreted form are removed from the N-terminus or C-terminus. Whether aparticular polypeptide lacking N- or C-terminal residues of a proteinretains such immunogenic activities can readily be determined by routinemethods described herein and otherwise known in the art.

Thus, the invention further includes polypeptide variants which show abiological or functional activity of the polypeptides of the invention(such as, for example, activity useful in detecting, preventing,diagnosing, prognosticating, treating, and/or amelioratingcardiovascular disorders). Such variants include deletions, insertions,inversions, repeats, and substitutions selected according to generalrules known in the art so as have little effect on activity.

The present application is directed to nucleic acid molecules at least80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleicacid sequences disclosed herein, (e.g., encoding a polypeptide havingthe amino acid sequence of an N and/or C terminal deletion),irrespective of whether they encode a polypeptide having functionalactivity. This is because even where a particular nucleic acid moleculedoes not encode a polypeptide having functional activity, one of skillin the art would still know how to use the nucleic acid molecule, forinstance, as a hybridization probe or a polymerase chain reaction (PCR)primer. Uses of the nucleic acid molecules of the present invention thatdo not encode a polypeptide having functional activity include, interalia, (1) isolating a gene or allelic or splice variants thereof in acDNA library; (2) in situ hybridization (e.g., “FISH”) to metaphasechromosomal spreads to provide precise chromosomal location of the gene,as described in Verma et al., Human Chromosomes: A Manual of BasicTechniques, Pergamon Press, New York (1988); (3) Northern Blot analysisfor detecting mRNA expression in specific tissues (e.g., normal ordiseased tissues); and (4) in situ hybridization (e.g., histochemistry)for detecting mRNA expression in specific tissues (e.g., normal ordiseased tissues).

Preferred, however, are nucleic acid molecules having sequences at least80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleicacid sequences disclosed herein, which do, in fact, encode a polypeptidehaving functional activity. By a polypeptide having “functionalactivity” is meant, a polypeptide capable of displaying one or moreknown functional activities associated with a full-length (complete)protein and/or a mature (secreted) protein of the invention. Suchfunctional activities include, but are not limited to, biologicalactivity (such as, for example, activity useful in detecting,preventing, diagnosing, prognosticating, treating, and/or amelioratingcardiovascular diseases and disorders), antigenicity (ability to bind,or compete with a polypeptide of the invention for binding, to ananti-polypeptide of the invention antibody), immunogenicity (ability togenerate antibody which binds to a specific polypeptide of theinvention), ability to form multimers with polypeptides of theinvention, and ability to bind to a receptor or ligand for a polypeptideof the invention.

The functional activity of the polypeptides, and fragments, variants andderivatives of the invention, can be assayed by various methods.

For example, in one embodiment where one is assaying for the ability tobind or compete with a full-length polypeptide of the present inventionfor binding to an anti-polypeptide antibody, various immunoassays knownin the art can be used, including but not limited to, competitive andnon-competitive assay systems using techniques such asradioimmunoassays, ELISA (enzyme linked immunosorbent assay), “sandwich”immunoassays, immunoradiometric assays, gel diffusion precipitationreactions, immunodiffusion assays, in situ immunoassays (using colloidalgold, enzyme or radioisotope labels, for example), western blots,precipitation reactions, agglutination assays (e.g., gel agglutinationassays, hemagglutination assays), complement fixation assays,immunofluorescence assays, protein A assays, and immunoelectrophoresisassays, etc. In one embodiment, antibody binding is detected bydetecting a label on the primary antibody. In another embodiment, theprimary antibody is detected by detecting binding of a secondaryantibody or reagent to the primary antibody. In a further embodiment,the secondary antibody is labeled. Many means are known in the art fordetecting binding in an immunoassay and are within the scope of thepresent invention.

In another embodiment, where a ligand is identified, or the ability of apolypeptide fragment, variant or derivative of the invention tomultimerize is being evaluated, binding can be assayed, e.g., by meanswell-known in the art, such as, for example, reducing and non-reducinggel chromatography, protein affinity chromatography, and affinityblotting. See generally, Phizicky et al., Microbiol. Rev. 59:94-123(1995). In another embodiment, the ability of physiological correlatesof a polypeptide of the present invention to bind to a substrate(s) ofthe polypeptide of the invention can be routinely assayed usingtechniques known in the art.

In addition, assays described herein (see Examples) and otherwise knownin the art may routinely be applied to measure the ability ofpolypeptides of the present invention and fragments, variants andderivatives thereof to elicit polypeptide related biological activity(either in vitro or in vivo). Other methods will be known to the skilledartisan and are within the scope of the invention.

Of course, due to the degeneracy of the genetic code, one of ordinaryskill in the art will immediately recognize that a large number of thenucleic acid molecules having a sequence at least 80%, 85%, 90%, 95%,96%, 97%, 98%, 99%, or 100% identical to, for example, the nucleic acidsequence of the cDNA contained in ATCC Deposit No:Z, the nucleic acidsequence referred to in Table 1B (SEQ ID NO:X), the nucleic acidsequence disclosed in Table 1A (e.g., the nucleic acid sequencedelineated in columns 7 and 8), the nucleic acid sequence disclosed inTable 2 (e.g., the nucleic acid sequence delineated in columns 8 and 9)or fragments thereof, will encode polypeptides “having functionalactivity.” In fact, since degenerate variants of any of these nucleotidesequences all encode the same polypeptide, in many instances, this willbe clear to the skilled artisan even without performing the abovedescribed comparison assay. It will be further recognized in the artthat, for such nucleic acid molecules that are not degenerate variants,a reasonable number will also encode a polypeptide having functionalactivity. This is because the skilled artisan is fully aware of aminoacid substitutions that are either less likely or not likely tosignificantly effect protein function (e.g., replacing one aliphaticamino acid with a second aliphatic amino acid), as further describedbelow.

For example, guidance concerning how to make phenotypically silent aminoacid substitutions is provided in Bowie et al., “Deciphering the Messagein Protein Sequences: Tolerance to Amino Acid Substitutions,” Science247:1306-1310 (1990), wherein the authors indicate that there are twomain strategies for studying the tolerance of an amino acid sequence tochange.

The first strategy exploits the tolerance of amino acid substitutions bynatural selection during the process of evolution. By comparing aminoacid sequences in different species, conserved amino acids can beidentified. These conserved amino acids are likely important for proteinfunction. In contrast, the amino acid positions where substitutions havebeen tolerated by natural selection indicates that these positions arenot critical for protein function. Thus, positions tolerating amino acidsubstitution could be modified while still maintaining biologicalactivity of the protein.

The second strategy uses genetic engineering to introduce amino acidchanges at specific positions of a cloned gene to identify regionscritical for protein function. For example, site directed mutagenesis oralanine-scanning mutagenesis (introduction of single alanine mutationsat every residue in the molecule) can be used. See Cunningham and Wells,Science 244:1081-1085(0.1989). The resulting mutant molecules can thenbe tested for biological activity.

As the authors state, these two strategies have revealed that proteinsare surprisingly tolerant of amino acid substitutions. The authorsfurther indicate which amino acid changes are likely to be permissive atcertain amino acid positions in the protein. For example, most buried(within the tertiary structure of the protein) amino acid residuesrequire nonpolar side chains, whereas few features of surface sidechains are generally conserved. Moreover, tolerated conservative aminoacid substitutions involve replacement of the aliphatic or hydrophobicamino acids Ala, Val, Leu and Ile; replacement of the hydroxyl residuesSer and Thr; replacement of the acidic residues Asp and Glu; replacementof the amide residues Asn and Gln, replacement of the basic residuesLys, Arg, and His; replacement of the aromatic residues Phe, Tyr, andTrp, and replacement of the small-sized amino acids Ala, Ser, Thr, Met,and Gly.

Besides conservative amino acid substitution, variants of the presentinvention include (i) substitutions with one or more of thenon-conserved amino acid residues, where the substituted amino acidresidues may or may not be one encoded by the genetic code, or (ii)substitutions with one or more of the amino acid residues having asubstituent group, or (iii) fusion of the mature polypeptide withanother compound, such as a compound to increase the stability and/orsolubility of the polypeptide (for example, polyethylene glycol), (iv)fusion of the polypeptide with additional amino acids, such as, forexample, an IgG Fc fusion region peptide, serum albumin (preferablyhuman serum albumin) or a fragment thereof, or leader or secretorysequence, or a sequence facilitating purification, or (v) fusion of thepolypeptide with another compound, such as albumin (including but notlimited to recombinant albumin (see, e.g., U.S. Pat. No. 5,876,969,issued Mar. 2, 1999, EP Patent 0 413 622, and U.S. Pat. No. 5,766,883,issued Jun. 16, 1998, herein incorporated by reference in theirentirety)). Such variant polypeptides are deemed to be within the scopeof those skilled in the art from the teachings herein.

For example, polypeptide variants containing amino acid substitutions ofcharged amino acids with other charged or neutral amino acids mayproduce proteins with improved characteristics, such as lessaggregation. Aggregation of pharmaceutical formulations both reducesactivity and increases clearance due to the aggregate's immunogenicactivity. See Pinckard et al., Clin. Exp. Immunol. 2:331-340 (1967);Robbins et al., Diabetes 36: 838-845 (1987); Cleland et al., Crit. Rev.Therapeutic Drug Carrier Systems 10:307-377 (1993).

A further embodiment of the invention relates to polypeptides whichcomprise the amino acid sequence of a polypeptide having an amino acidsequence which contains at least one amino acid substitution, but notmore than 50 amino acid substitutions, even more preferably, not morethan 40 amino acid substitutions, still more preferably, not more than30 amino acid substitutions, and still even more preferably, not morethan 20 amino acid substitutions from a polypeptide sequence disclosedherein. Of course it is highly preferable for a polypeptide to have anamino acid sequence which, for example, comprises the amino acidsequence of a polypeptide of SEQ ID NO:Y, the amino acid sequence of themature (e.g., secreted) polypeptide of SEQ ID NO:Y, an amino acidsequence encoded by SEQ ID NO:X, an amino acid sequence encoded by theportion of SEQ ID NO:X as defined in columns 8 and 9 of Table 2, anamino acid sequence encoded by the complement of SEQ ID NO:X, an aminoacid sequence encoded by cDNA contained in ATCC Deposit No:Z, and/or theamino acid sequence of a mature (secreted) polypeptide encoded by cDNAcontained in ATCC Deposit No:Z, or a fragment thereof, which contains,in order of ever-increasing preference, at least one, but not more than10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid substitutions.

In specific embodiments, the polypeptides of the invention comprise, oralternatively, consist of, fragments or variants of a reference aminoacid sequence selected from: (a) the amino acid sequence of SEQ ID NO:Yor fragments thereof (e.g., the mature formand/or other fragmentsdescribed herein); (b) the amino acid sequence encoded by SEQ ID NO:X orfragments thereof; (c) the amino acid sequence encoded by the complementof SEQ ID NO:X or fragments thereof; (d) the amino acid sequence encodedby the portion of SEQ ID NO:X as defined in columns 8 and 9 of Table 2or fragments thereof; and (e) the amino acid sequence encoded by cDNAcontained in ATCC Deposit No:Z or fragments thereof; wherein thefragments or variants have 1-5,5-10, 5-25, 5-50, 10-50 or 50-150, aminoacid residue additions, substitutions, and/or deletions when compared tothe reference amino acid sequence. In preferred embodiments, the aminoacid substitutions are conservative. Polynucleotides encoding thesepolypeptides are also encompassed by the invention.

Polynucleotide and Polypeptide Fragments

The present invention is also directed to polynucleotide fragments ofthe polynucleotides (nucleic acids) of the invention. In the presentinvention, a “polynucleotide fragment” refers to a polynucleotide havinga nucleic acid sequence which, for example: is a portion of the cDNAcontained in ATCC Deposit No:Z or, the complementary strand thereto; isa portion of the polynucleotide sequence encoding the polypeptideencoded by the cDNA contained in ATCC Deposit No:Z or the complementarystrand thereto; is a portion of the polynucleotide sequence encoding themature (secreted) polypeptide encoded by the cDNA contained in ATCCDeposit No:Z or the complementary strand thereto; is a portion of apolynucleotide sequence encoding the mature amino acid sequence asdefined in columns 14 and 15 of Table 1A or the complementary strandthereto; is a portion of a polynucleotide sequence encoding the aminoacid sequence encoded by the region of SEQ ID NO:X as defined in columns8 and 9 of Table 2 or the complementary strand thereto; is a portion ofthe polynucleotide sequence of SEQ ID NO:X as defined in columns 8 and 9of Table 2 or the complementary strand thereto; is a portion of thepolynucleotide sequence in SEQ ID NO:X or the complementary strandthereto; is a polynucleotide sequence encoding a portion of thepolypeptide of SEQ ID NO:Y; is a polynucleotide sequence encoding aportion of a polypeptide encoded by SEQ ID NO:X; is a polynucleotidesequence encoding a portion of a polypeptide encoded by the complementof the polynucleotide sequence in SEQ ID NO:X; is a portion of apolynucleotide sequence encoding the amino acid sequence encoded by theregion of SEQ ID NO:B as defined in column 6 of Table 1C or thecomplementary strand thereto; or is a portion of the polynucleotidesequence of SEQ ID NO:B as defined in column 6 of Table 1C or thecomplementary strand thereto.

The polynucleotide fragments of the invention are preferably at leastabout 15 nt, and more preferably at least about 20 nt, still morepreferably at least about 30 nt, and even more preferably, at leastabout 40 nt, at least about 50 nt, at least about 75 nt, or at leastabout 150 nt in length. A fragment “at least 20 nt in length,” forexample, is intended to include 20 or more contiguous bases from thecDNA sequence contained in ATCC Deposit No:Z, or the nucleotide sequenceshown in SEQ ID NO:X or the complementary stand thereto. In this context“about” includes the particularly recited value or a value larger orsmaller by several (5, 4, 3, 2, or 1) nucleotides, at either terminus orat both termini. These nucleotide fragments have uses that include, butare not limited to, as diagnostic probes and primers as discussedherein. Of course, larger fragments (e.g., at least 160, 170, 180, 190,200, 250, 500, 600, 1000, or 2000 nucleotides in length) are alsoencompassed by the invention.

Moreover, representative examples of polynucleotide fragments of theinvention comprise, or alternatively consist of, a sequence from aboutnucleotide number 1-50, 51-100, 101-150, 151-200, 201-250, 251-300,301-350, 351-400, 401-450, 451-500, 501-550, 551-600, 601-650, 651-700,701-750, 751-800, 801-850, 851-900, 901-950, 951-1000, 1001-1050,1051-1100, 1101-1150, 1151-1200, 1201-1250, 1251-1300, 1301-1350,1351-1400, 1401-1450, 1451-1500, 1501-1550, 1551-1600, 1601-1650,1651-1700, 1701-1750, 1751-1800, 1801-1850, 1851-1900, 1901-1950,1951-2000, 2001-2050, 2051-2100, 2101-2150, 2151-2200, 2201-2250,2251-2300, 2301-2350, 2351-2400, 2401-2450, 2451-2500, 2501-2550,2551-2600, 2601-2650, 2651-2700, 2701-2750, 2751-2800, 2801-2.850,2851-2900, 2901-2950, 2951-3000, 3001-3050, 3051-3100, 3101-3150,3151-3200, 3201-3250, 3251-3300, 3301-3350, 3351-3400, 3401-3450,3451-3500, 3501-3550, 3551-3600, 3601-3650, 3651-3700, 3701-3750,3751-3800, 3801-3850, 3851-3900, 3901-3950, 3951-4000, 4001-4050,4051-4100, 4101-4150, 41514200, 42014250, 4251-4300, 4301-4350,4351-4400, 4401-4450, 4451-4500, 4501-4550, 4551-4600, 4601-4650,4651-4700, 4701-4750, 4751-4800, 4801-4850, 4851-4900, 4901-4950,4951-5000, 5001-5050, 5051-5100, 5101-5150, 5151-5200, 5201-5250,5251-5300, 5301-5350, 5351-5400, 5401-5450, 5451-5500, 5501-5550,5551-5600, 5601-5650, 5651-5700, 5701-5750, 5751-5800, 5801-5850,5851-5900, 5901-5950, 5951-6000, 6001-6050, 6051-6100, 6101-6150,6151-6200, 6201-6250, 6251-6300, 6301-6350, 6351-6400, 6401-6450,6451-6500, 6501-6550, 6551-6600, 6601-6650, 6651-6700, 6701-6750,6751-6800, 6801-6850, 6851-6900, 6901-6950, 6951-7000, 7001-7050,7051-7100, 7101-7150, 7151-7200, 7201-7250, 7251-7300 or 7301 to the endof SEQ ID NO:X, or the complementary strand thereto. In this context“about” includes the particularly recited range or a range larger orsmaller by several (5, 4, 3, 2, or 1) nucleotides, at either terminus orat both termini. Preferably, these fragments encode a polypeptide whichhas a functional activity (e.g., biological activity; such as, forexample, activity useful in detecting, preventing, diagnosing,prognosticating, treating, and/or ameliorating cardiovascular diseasesand disorders). More preferably, these polynucleotides can be used asprobes or primers as discussed herein. Polynucleotides which hybridizeto one or more of these polynucleotides under stringent hybridizationconditions or alternatively, under lower stringency conditions are alsoencompassed by the invention, as are polypeptides encoded by thesepolynucleotides.

Further representative examples of polynucleotide fragments of theinvention comprise, or alternatively consist of, a sequence from aboutnucleotide number 1-50, 51-100, 101-150, 151-200, 201-250, 251-300,301-350, 351-400, 401-450, 451-500, 501-550, 551-600, 601-650, 651-700,701-750, 751-800, 801-850, 851-900, 901-950, 951-1000, 1001-1050,1051-1100, 1101-1150, 1151-1200, 1201-1250, 1251-1300, 1301-1350,1351-1400, 1401-1450, 1451-1500, 1501-1550, 1551-1600, 1601-1650,1651-1700, 1701-1750, 1751-1800, 1801-1850, 1851-1900, 1901-1950,1951-2000, 2001-2050, 2051-2100, 2101-2150, 2151-2200, 2201-2250,2251-2300, 2301-2350, 2351-2400, 2401-2450, 2451-2500, 2501-2550,2551-2600, 2601-2650, 2651-2700, 2701-2750, 2751-2800, 2801-2850,2851-2900, 2901-2950, 2951-3000, 3001-3050, 3051-3100, 3101-3150,3151-3200, 3201-3250, 3251-3300, 3301-3350, 3351-3400, 3401-3450,3451-3500, 3501-3550, 3551-3600, 3601-3650, 3651-3700, 3701-3750,3751-3800, 3801-3850, 3851-3900, 3901-3950, 3951-4000, 4001-4050,4051-4100, 4101-4150, 4151-4200, 4201-4250, 4251-4300, 4301-4350,4351-4400, 4401-4450, 4451-4500, 4501-4550, 4551-4600, 4601-4650,4651-4700, 4701-4750, 4751-4800, 48014850, 4851-4900, 4901-4950,4951-5000, 5001-5050, 5051-5100, 5101-5150, 5151-5200, 5201-5250,5251-5300, 5301-5350, 5351-5400, 5401-5450, 5451-5500, 5501-5550,5551-5600, 5601-5650, 5651-5700, 5701-5750, 5751-5800, 5801-5850,5851-5900, 5901-5950, 5951-6000, 6001-6050, 6051-6100, 6101-6150,6151-6200, 6201-6250, 6251-6300, 6301-6350, 6351-6400, 6401-6450,6451-6500, 6501-6550, 6551-6600, 6601-6650, 6651-6700, 6701-6750,6751-6800, 6801-6850, 6851-6900, 6901-6950, 6951-7000, 7001-7050,7051-7100, 7101-7150, 7151-7200, 7201-7250, 7251-7300 or 7301 to the endof the cDNA sequence contained in ATCC Deposit No:Z, or thecomplementary strand thereto. In this context “about” includes theparticularly recited range or a range larger or smaller by several (5,4, 3, 2, or 1) nucleotides, at either terminus or at both termini.Preferably, these fragments encode a polypeptide which has a functionalactivity (e.g., biological activity). More preferably, thesepolynucleotides can be used as probes or primers as discussed herein.Polynucleotides which hybridize to one or more of these polynucleotidesunder stringent hybridization conditions or alternatively, under lowerstringency conditions are also encompassed by the invention, as arepolypeptides encoded by these polynucleotides.

Moreover, representative examples of polynucleotide fragments of theinvention comprise, or alternatively consist of, a nucleic acid sequencecomprising one, two, three, four, five, six, seven, eight, nine, ten, ormore of the above described polynucleotide fragments of the invention incombination with a polynucleotide sequence delineated in Table 1C column6. Additional, representative examples of polynucleotide fragments ofthe invention comprise, or alternatively consist of, a nucleic acidsequence comprising one, two, three, four, five, six, seven, eight,nine, ten, or more of the above described polynucleotide fragments ofthe invention in combination with a polynucleotide sequence that is thecomplementary strand of a sequence delineated in column 6 of Table 1C.In further embodiments, the above-described polynucleotide fragments ofthe invention comprise, or alternatively consist of, sequencesdelineated in Table 1C, column 6, and have a nucleic acid sequence whichis different from that of the BAC fragment having the sequence disclosedin SEQ ID NO:B (see Table 1C, column 5). In additional embodiments, theabove-described polynucleotide fragments of the invention comprise, oralternatively consist of, sequences delineated in Table 1C, column 6,and have a nucleic acid sequence which is different from that publishedfor the BAC clone identified as BAC ID NO:A (see Table 1C, column 4). Inadditional embodiments, the above-described polynucleotides of theinvention comprise, or alternatively consist of, sequences delineatedTable 1C, column 6, and have a nucleic acid sequence which is differentfrom that contained in the BAC clone identified as BAC ID NO:A (seeTable 1C, column 4). Polypeptides encoded by these polynucleotides,other polynucleotides that encode these polypeptides, and antibodiesthat bind these polypeptides are also encompassed by the invention.Additionally, fragments and variants of the above-describedpolynucleotides and polypeptides are also encompassed by the invention.

In additional specific embodiments, polynucleotides of the inventioncomprise, or alternatively consist of, one, two, three, four, five, six,seven, eight, nine, ten, or more fragments of the sequences delineatedin column 6 of Table 1C, and the polynucleotide sequence of SEQ ID NO:X(e.g., as defined in Table 1C, column 2) or fragments or variantsthereof. Polypeptides encoded by these polynucleotides, otherpolynucleotides that encode these polypeptides, and antibodies that bindthese polypeptides are also encompassed by the invention.

In additional specific embodiments, polynucleotides of the inventioncomprise, or alternatively consist of, one, two, three, four, five, six,seven, eight, nine, ten, or more fragments of the sequences delineatedin column 6′ of Table 1C which correspond to the same ATCC Deposit No:Z(see Table 1C, column 1), and the polynucleotide sequence of SEQ ID NO:X(e.g., as defined in Table 1A, 1B, or 1C) or fragments or variantsthereof. Polypeptides encoded by these polynucleotides, otherpolynucleotides that encode these polypeptides, and antibodies that bindthese polypeptides are also encompassed by the invention.

In further specific embodiments, polynucleotides of the inventioncomprise, or alternatively consist of, one, two, three, four, five, six,seven, eight, nine, ten, or more fragments of the sequences delineatedin the same row of column 6 of Table 1C, and the polynucleotide sequenceof SEQ ID NO:X (e.g., as defined in Table 1A, 1B, or 1C) or fragments orvariants thereof. Polypeptides encoded by these polynucleotides, otherpolynucleotides that encode these polypeptides, and antibodies that bindthese polypeptides are also encompassed by the invention.

In additional specific embodiments, polynucleotides of the inventioncomprise, or alternatively consist of a polynucleotide sequence in whichthe 3′ 10 polynucleotides of one of the sequences delineated in column 6of Table 1C and the 5′ 10 polynucleotides of the sequence of SEQ ID NO:Xare directly contiguous. Nucleic acids which hybridize to the complementof these 20 contiguous polynucleotides under stringent hybridizationconditions or alternatively, under lower stringency conditions, are alsoencompassed by the invention. Polypeptides encoded by thesepolynucleotides and/or nucleic acids, other polynucleotides and/ornucleic acids that encode these polypeptides, and antibodies that bindthese polypeptides are also encompassed by the invention. Additionally,fragments and variants of the above-described polynucleotides, nucleicacids, and polypeptides are also encompassed by the invention.

In additional specific embodiments, polynucleotides of the inventioncomprise, or alternatively consist of a polynucleotide sequence in whichthe 3′ 10 polynucleotides of one of the sequences delineated in column 6of Table 1C and the 5′ 10 polynucleotides of a fragment or variant ofthe sequence of SEQ ID NO:X (e.g., as described herein) are directlycontiguous Nucleic acids which hybridize to the complement of these 20contiguous polynucleotides under stringent hybridization conditions oralternatively, under lower stringency conditions, are also encompassedby the invention. Polypeptides encoded by these polynucleotides and/ornucleic acids, other polynucleotides and/or nucleic acids encoding thesepolypeptides, and antibodies that bind these polypeptides are alsoencompassed by the invention. Additionally, fragments and variants ofthe above-described polynucleotides, nucleic acids, and polypeptides arealso encompassed by the invention.

In further specific embodiments, polynucleotides of the inventioncomprise, or alternatively consist of a polynucleotide sequence in whichthe 3′ 10 polynucleotides of a fragment or variant of the sequence ofSEQ ID NO:X and the 5′ 10 polynucleotides of the sequence of one of thesequences delineated in column 6 of Table 1C are directly contiguous.Nucleic acids which hybridize to the complement of these 20 contiguouspolynucleotides under stringent hybridization conditions oralternatively, under lower stringency conditions, are also encompassedby the invention. Polypeptides encoded by these polynucleotides and/ornucleic acids, other polynucleotides and/or nucleic acids encoding thesepolypeptides, and antibodies that bind these polypeptides are alsoencompassed by the invention. Additionally, fragments and variants ofthe above-described polynucleotides, nucleic acids, and polypeptides arealso encompassed by the invention.

In specific embodiments, polynucleotides of the invention comprise, oralternatively consist of a polynucleotide sequence in which the 3′ 10polynucleotides of one of the sequences delineated in column 6 of Table1C and the 5′ 10 polynucleotides of another sequence in column 6 aredirectly contiguous. In preferred embodiments, the 3′ 10 polynucleotidesof one of the sequences delineated in column 6 of Table 1C is directlycontiguous with the 5′ 10 polynucleotides of the next sequential exondelineated in Table 1C, column 6. Nucleic acids which hybridize to thecomplement of these 20 contiguous polynucleotides under stringenthybridization conditions or alternatively, under lower stringencyconditions, are also encompassed by the invention. Polypeptides encodedby these polynucleotides and/or nucleic acids, other polynucleotidesand/or nucleic acids encoding these polypeptides, and antibodies thatbind these polypeptides are also encompassed by the invention.Additionally, fragments and variants of the above-describedpolynucleotides, nucleic acids, and polypeptides are also encompassed bythe invention.

In the present invention, a “polypeptide fragment” refers to an aminoacid sequence which is a portion of the amino acid sequence contained inSEQ ID NO:Y, is a portion of the mature form of SEQ ID NO:Y as definedin columns 14 and 15 of Table 1A, a portion of an amino acid sequenceencoded by the portion of SEQ ID NO:X as defined in columns 8 and 9 ofTable 2, is a portion of an amino acid sequence encoded by thepolynucleotide sequence of SEQ ID NO:X, is a portion of an amino acidsequence encoded by the complement of the polynucleotide sequence in SEQID NO:X, is a portion of the amino acid sequence of a mature (secreted)polypeptide encoded by the cDNA contained in ATCC Deposit No:Z, and/oris a portion of an amino acid sequence encoded by the cDNA contained inATCC Deposit No:Z. Protein (polypeptide) fragments may be“free-standing,” or comprised within a larger polypeptide of which thefragment forms a part or region, most preferably as a single continuousregion. Representative examples of polypeptide fragments of theinvention, include, for example, fragments comprising, or alternativelyconsisting of, from about amino acid number 1-20, 21-40, 41-60, 61-80,81-100, 101-120, 121-140, 141-160, 161-180, 181-200, 201-220, 221-240,241-260, 261-280, 281-300, 301-320, 321-340, 341-360, 361-380, 381-400,401-420, 421-440, 441-460, 461-480, 481-500, 501-520, 521-540, 541-560,561-580, 581-600, 601-620, 621-640, 641-660, 661-680, 681-700, 701-720,721-740, 741-760, 761-780, 781-800, 801-820, 821-840, 841-860, 861-880,881-900, 901-920, 921-940, 941-960, 961-980, 981-1000, 1001-1020,1021-1040, 1041-1060, 1061-1080, 1081-1100, 1101-1120, 1121-1140,1141-1160, 1161-1180, 1181-1200, 1201-1220, 1221-1240, 1241-1260,1261-1280, 1281-1300, 1301-1320, 1321-1340, 1341-1360, 1361-1380,1381-1400, 1401-1420, 1421-1440, or 1441 to the end of the coding regionof cDNA and SEQ ID NO: Y. In a preferred embodiment, polypeptidefragments of the invention include, for example, fragments comprising,or alternatively consisting of, from about amino acid number 1-20,21-40, 41-60, 61-80, 81-100, 101-120, 121-140, 141-160, 161-180,181-200, 201-220, 221-240, 241-260, 261-280, 281-300, 301-320, 321-340,341-360, 361-380, 381-400, 401-420, 421-440, 441-460, 461-480, 481-500,501-520, 521-540, 541-560, 561-580, 581-600, 601-620, 621-640, 641-660,661-680, 681-700, 701-720, 721-740, 741-760, 761-780, 781-800, 801-820,821-840, 841-860, 861-880, 881-900, 901-920, 921-940, 941-960, 961-980,981-1000, 1001-1020, 1021-1040, 1041-1060, 1061-1080, 1081-1100,1101-1120, 1121-1140, 1141-1160, 1161-1180, 1181-1200, 1201-1220,1221-1240, 1241-1260, 1261-1280, 1281-1300, 1301-1320, 1321-1340,1341-1360, 1361-1380, 1381-1400, 1401-1420, 1421-1440, or 1441 to theend of the coding region of SEQ ID NO:Y. Moreover, polypeptide fragmentsof the invention may be at least about 10, 15, 20, 25, 30, 35, 40, 45,50, 55, 60, 65, 70, 75, 80, 85, 90, 100, 110, 120, 130, 140, or 150amino acids in length. In this context “about” includes the particularlyrecited ranges or values, or ranges or values larger or smaller byseveral (5, 4, 3, 2, or 1) amino acids, at either extreme or at bothextremes. Polynucleotides encoding these polypeptide fragments are alsoencompassed by the invention.

Even if deletion of one or more amino acids from the N-terminus of aprotein results in modification of loss of one or more biologicalfunctions of the protein, other functional activities (e.g., biologicalactivities; such as, for example, activity useful in detecting,preventing, diagnosing, prognosticating, treating, and/or amelioratingcardiovascular diseases and disorders; ability to multimerize; abilityto bind a ligand; antigenic ability useful for production of polypeptidespecific antibodies) may still be retained. For example, the ability ofshortened muteins to induce and/or bind to antibodies which recognizethe complete or mature forms of the polypeptides generally will beretained when less than the majority of the residues of the complete ormature polypeptide are removed from the N-terminus. Whether a particularpolypeptide lacking N-terminal residues of a complete polypeptideretains such immunologic activities can readily be determined by routinemethods described herein and otherwise known in the art. It is notunlikely that a mutein with a large number of deleted N-terminal aminoacid residues may retain some biological or immunogenic activities. Infact, peptides composed of as few as six amino acid residues may oftenevoke an immune response.

Accordingly, polypeptide fragments include the secreted protein as wellas the mature form. Further preferred polypeptide fragments include thesecreted protein or the mature form having a continuous series ofdeleted residues from the amino or the carboxy terminus, or both. Forexample, any number of amino acids, ranging from 1-60, can be deletedfrom the amino terminus of either the secreted polypeptide or the matureform. Similarly, any number of amino acids, ranging from 1-30, can bedeleted from the carboxy terminus of the secreted protein or matureform. Furthermore, any combination of the above amino and carboxyterminus deletions are preferred. Similarly, polynucleotides encodingthese polypeptide fragments are also preferred.

The present invention further provides polypeptides having one or moreresidues deleted from the amino terminus of the amino acid sequence of apolypeptide disclosed herein (e.g., a polypeptide of SEQ ID NO:Y, apolypeptide as defined in columns 14 and 15 of Table 1A, a polypeptideencoded by the polynucleotide sequence contained in SEQ ID NO:X or thecomplement thereof, a polypeptide encoded by the portion of SEQ ID NO:Xas defined in columns 8 and 9 of Table 2, a polypeptide encoded by theportion of SEQ ID NO:B as defined in column 6 of Table 1C, a polypeptideencoded by the cDNA contained in ATCC Deposit No:Z, and/or a maturepolypeptide encoded by the cDNA contained in ATCC Deposit No:Z). Inparticular, N-terminal deletions may be described by the general formulam-q, where q is a whole integer representing the total number of aminoacid residues in a polypeptide of the invention (e.g., the polypeptidedisclosed in SEQ ID NO:Y, the mature (secreted) portion of SEQ ID NO:Yas defined in columns 14 and 15 of Table 1A, or the polypeptide encodedby the portion of SEQ ID NO:X as defined in columns 8 and 9 of Table 2),and m is defined as any integer ranging from 2 to q-6. Polynucleotidesencoding these polypeptides are also encompassed by the invention.

The present invention further provides polypeptides having one or moreresidues from the carboxy terminus of the amino acid sequence of apolypeptide disclosed herein (e.g., a polypeptide of SEQ ID NO:Y, themature (secreted) portion of SEQ ID NO:Y as defined in columns 14 and 15of Table 1A, a polypeptide encoded by the polynucleotide sequencecontained in SEQ ID NO:X, a polypeptide encoded by the portion of SEQ IDNO:X as defined in columns 8 and 9 of Table 2, a polypeptide encoded bythe portion of SEQ ID NO:B as defined in column 6 of Table 1C, apolypeptide encoded by the cDNA contained in ATCC Deposit No:Z, and/or amature polypeptide encoded by the cDNA contained in ATCC Deposit No:Z).In particular, C-terminal deletions may be described by the generalformula 1-n, where n is any whole integer ranging from 6 to q-1, andwhere n corresponds to the position of amino acid residue in apolypeptide of the invention. Polynucleotides encoding thesepolypeptides are also encompassed by the invention.

In addition, any of the above described N- or C-terminal deletions canbe combined to produce a N- and C-terminal deleted polypeptide. Theinvention also provides polypeptides having one or more amino acidsdeleted from both the amino and the carboxyl termini, which may bedescribed generally as having residues m-n of a polypeptide encoded bySEQ ID NO:X (e.g., including, but not limited to, the preferredpolypeptide disclosed as SEQ ID NO:Y, the mature (secreted) portion ofSEQ ID NO:Y as defined in columns 14 and 15 of Table 1A, and thepolypeptide encoded by the portion of SEQ ID NO:X as defined in columns8 and 9 of Table 2), the cDNA contained in ATCC Deposit No:Z, and/or thecomplement thereof, where n and m are integers as described above.Polynucleotides encoding these polypeptides are also encompassed by theinvention.

Also as mentioned above, even if deletion of one or more amino acidsfrom the C-terminus of a protein results in modification of loss of oneor more biological functions of the protein, other functional activities(e.g., biological activities such as, for example, activity useful indetecting, preventing, diagnosing, prognosticating, treating, and/orameliorating cardiovascular diseases and disorders; ability tomultimerize; ability to bind a ligand; antigenic ability useful forproduction of polypeptide specific antibodies) may still be retained.For example the ability of the shortened mutein to induce and/or bind toantibodies which recognize the complete or mature forms of thepolypeptide generally will be retained when less than the majority ofthe residues of the complete or mature polypeptide are removed from theC-terminus. Whether a particular polypeptide lacking C-terminal residuesof a complete polypeptide retains such immunologic activities canreadily be determined by routine methods described herein and otherwiseknown in the art. It is not unlikely that a mutein with a large numberof deleted C-terminal amino acid residues may retain some biological orimmunogenic activities. In fact, peptides composed of as few as sixamino acid residues may often evoke an immune response.

The present application is also directed to proteins containingpolypeptides at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identicalto a polypeptide sequence set forth herein. In preferred embodiments,the application is directed to proteins containing polypeptides at least80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to polypeptideshaving the amino acid sequence of the specific N- and C-terminaldeletions. Polynucleotides encoding these polypeptides are alsoencompassed by the invention.

Any polypeptide sequence encoded by, for example, the polynucleotidesequences set forth as SEQ ID NO:X or the complement thereof,(presented, for example, in Tables 1A and 2), the cDNA contained in ATCCDeposit No:Z, or the polynucleotide sequence as defined in column 6 ofTable 1C, may be analyzed to determine certain preferred regions of thepolypeptide. For example, the amino acid sequence of a polypeptideencoded by a polynucleotide sequence of SEQ ID NO:X (e.g., thepolypeptide of SEQ ID NO:Y and the polypeptide encoded by the portion ofSEQ ID NO:X as defined in columns 8 and 9 of Table 2) or the cDNAcontained in ATCC Deposit No:Z may be analyzed using the defaultparameters of the DNASTAR computer algorithm (DNASTAR, Inc., 1228 S.Park St., Madison, Wis. 53715 USA; http://www.dnastar.com/).

Polypeptide regions that may be routinely obtained using the DNASTARcomputer algorithm include, but are not limited to, Garnier-Robsonalpha-regions, beta-regions, turn-regions, and coil-regions; Chou-Fasmanalpha-regions, beta-regions, and turn-regions; Kyte-Doolittlehydrophilic regions and hydrophobic regions; Eisenberg alpha- andbeta-amphipathic regions; Karplus-Schulz flexible regions; Eminisurface-forming regions; and Jameson-Wolf regions of high antigenicindex. Among highly preferred polynucleotides of the invention in thisregard are those that encode polypeptides comprising regions thatcombine several structural features, such as several (e.g., 1, 2, 3 or4) of the features set out above.

Additionally, Kyte-Doolittle hydrophilic regions and hydrophobicregions, Emini surface-forming regions, and Jameson-Wolf regions of highantigenic index (i.e., containing four or more contiguous amino acidshaving an antigenic index of greater than or equal to 1.5, as identifiedusing the default parameters of the Jameson-Wolf program) can routinelybe used to determine polypeptide regions that exhibit a high degree ofpotential for antigenicity. Regions of high antigenicity are determinedfrom data by DNASTAR analysis by choosing values which represent regionsof the polypeptide which are likely to be exposed on the surface of thepolypeptide in an environment in which antigen recognition may occur inthe process of initiation of an immune response.

Preferred polypeptide fragments of the invention are fragmentscomprising, or alternatively, consisting of, an amino acid sequence thatdisplays a functional activity (e.g. biological activity such as, forexample, activity useful in detecting, preventing, diagnosing,prognosticating, treating, and/or ameliorating cardiovascular diseasesand disorders; ability to multimerize; ability to bind a ligand;antigenic ability-useful for production of polypeptide specificantibodies) of the polypeptide sequence of which the amino acid sequenceis a fragment. By a polypeptide displaying a “functional activity” ismeant a polypeptide capable of one or more known functional activitiesassociated with a full-length protein, such as, for example, biologicalactivity, antigenicity, immunogenicity, and/or multimerization, asdescribed herein.

Other preferred polypeptide fragments are biologically active fragments.Biologically active fragments are those exhibiting activity similar, butnot necessarily identical, to an activity of the polypeptide of thepresent invention. The biological activity of the fragments may includean improved desired activity, or a decreased undesirable activity.

In preferred embodiments, polypeptides of the invention comprise, oralternatively consist of, one, two, three, four, five or more of theantigenic fragments of the polypeptide of SEQ D NO:Y, or portionsthereof. Polynucleotides encoding these polypeptides are alsoencompassed by the invention.

Epitopes and Antibodies

The present invention encompasses polypeptides comprising, oralternatively consisting of, an epitope of: the polypeptide sequenceshown in SEQ ID NO:Y; a polypeptide sequence encoded by SEQ ID NO:X orthe complementary strand thereto; the polypeptide sequence encoded bythe portion of SEQ ID NO:X as defined in columns 8 and 9 of Table 2; thepolypeptide sequence encoded by the portion of SEQ D NO:B as defined incolumn 6 of Table 1C or the complement thereto; the polypeptide sequenceencoded by the cDNA contained in ATCC Deposit No:Z; or the polypeptidesequence encoded by a polynucleotide that hybridizes to the sequence ofSEQ ID NO:X, the complement of the sequence of SEQ ID NO:X, thecomplement of a portion of SEQ ID NO:X as defined in columns 8 and 9 ofTable 2, or the cDNA sequence contained in ATCC Deposit No:Z understringent hybridization conditions or alternatively, under lowerstringency hybridization as defined supra. The present invention furtherencompasses polynucleotide sequences encoding an epitope of apolypeptide sequence of the invention (such as, for example, thesequence disclosed in SEQ ID NO:X, or a fragment thereof),polynucleotide sequences of the complementary strand of a polynucleotidesequence encoding an epitope of the invention, and polynucleotidesequences which hybridize to the complementary strand under stringenthybridization conditions or alternatively, under lower stringencyhybridization conditions defined supra.

The term “epitopes,” as used herein, refers to portions of a polypeptidehaving antigenic or immunogenic activity in an animal, preferably amammal, and most preferably in a human. In a preferred embodiment, thepresent invention encompasses a polypeptide comprising an epitope, aswell as the polynucleotide encoding this polypeptide. An “immunogenicepitope,” as used herein, is defined as a portion of a protein thatelicits an antibody response in an animal, as determined by any methodknown in the art, for example, by the methods for generating antibodiesdescribed infra. (See, for example, Geysen et al., Proc. Natl. Acad.Sci. USA 81:3998-4002 (1983)). The term “antigenic epitope,” as usedherein, is defined as a portion of a protein to which an antibody canimmunospecifically bind its antigen as determined by any method wellknown in the art, for example, by the immunoassays described herein.Immunospecific binding excludes non-specific binding but does notnecessarily exclude cross-reactivity with other antigens. Antigenicepitopes need not necessarily be immunogenic.

Fragments which function as epitopes may be produced by any conventionalmeans. (See, e.g., Houghten, R. A., Proc. Natl. Acad. Sci. USA82:5131-5135 (1985) further described in U.S. Pat. No. 4,631,211.)

In the present invention, antigenic epitopes preferably contain asequence of at least 4, at least 5, at least 6, at least 7, morepreferably at least 8, at least 9, at least 10, at least 11, at least12, at least 13, at least 14, at least 15, at least 20, at least 25, atleast 30, at least 40, at least 50, and, most preferably, between about15 to about 30 amino acids. Preferred polypeptides comprisingimmunogenic or antigenic epitopes are at least 10, 15, 20, 25, 30, 35,40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 amino acidresidues in length. Additional non-exclusive preferred antigenicepitopes include the antigenic epitopes disclosed herein, as well asportions thereof. Antigenic epitopes are useful, for example, to raiseantibodies, including monoclonal antibodies, that specifically bind theepitope. Preferred antigenic epitopes include the antigenic epitopesdisclosed herein, as well as any combination of two, three, four, fiveor more of these antigenic epitopes. Antigenic epitopes can be used asthe target molecules in immunoassays. (See, for instance, Wilson et al.,Cell 37:767-778 (1984); Sutcliffe et al., Science 219:660-666 (1983)).

Non-limiting examples of epitopes of polypeptides that can be used togenerate antibodies of the invention include a polypeptide comprising,or alternatively consisting of, at least one, two, three, four, five,six or more of the portion(s) of SEQ ED NO:Y specified in Table 1B.These polypeptide fragments have been determined to bear antigenicepitopes of the proteins of the invention by the analysis of theJameson-Wolf antigenic index which is included in the DNAStar suite ofcomputer programs. By “comprise” it is intended that a polypeptidecontains at least one, two, three, four, five, six or more of theportion(s) of SEQ ID NO:Y shown in Table 1B, but it may containadditional flanking residues on either the amino or carboxyl termini ofthe recited portion. Such additional flanking sequences are preferablysequences naturally found adjacent to the portion; i.e., contiguoussequence shown in SEQ ID NO:Y. The flanking sequence may, however, besequences from a heterologous polypeptide, such as from another proteindescribed herein or from a heterologous polypeptide not describedherein. In particular embodiments, epitope portions of a polypeptide ofthe invention comprise one, two, three, or more of the portions of SEQID NO:Y shown in Table 1B.

Similarly, immunogenic epitopes can be used, for example, to induceantibodies according to methods well known in the art. See, forinstance, Sutcliffe et al., supra; Wilson et al., supra; Chow et al.,Proc. Natl. Acad. Sci. USA 82:910-914; and Bittle et al., J. Gen. Virol.66:2347-2354 (1985). Preferred immunogenic epitopes include theimmunogenic epitopes disclosed herein, as well as any combination oftwo, three, four, five or more of these immunogenic epitopes. Thepolypeptides comprising one or more immunogenic epitopes may bepresented for eliciting an antibody response together with a carrierprotein, such as an albumin, to an animal system (such as rabbit ormouse), or, if the polypeptide is of sufficient length (at least about25 amino acids), the polypeptide may be presented without a carrier.However, immunogenic epitopes comprising as few as 8 to 10 amino acidshave been shown to be sufficient to raise antibodies capable of bindingto, at the very least, linear epitopes in a denatured polypeptide (e.g.,in Western blotting).

Epitope-bearing polypeptides of the present invention may be used toinduce antibodies according to methods well known in the art including,but not limited to, in vivo immunization, in vitro immunization, andphage display methods. See, e.g., Sutcliffe et al., supra; Wilson etal., supra, and Bittle et al., J. Gen. Virol., 66:2347-2354 (1985). Ifin vivo immunization is used, animals may be immunized with freepeptide; however, anti-peptide antibody titer may be boosted by couplingthe peptide to a macromolecular carrier, such as keyhole limpethemacyanin (KLH) or tetanus toxoid. For instance, peptides containingcysteine residues may be coupled to a carrier using a linker such asmaleimidobenzoyl-N-hydroxysuccinimide ester (MBS), while other peptidesmay be coupled to carriers using a more general linking agent such asglutaraldehyde. Animals such as rabbits, rats and mice are immunizedwith either free or carrier-coupled peptides, for instance, byintraperitoneal and/or intradermal injection of emulsions containingabout 100 μg of peptide or carrier protein and Freund's adjuvant or anyother adjuvant known for stimulating an immune response. Several boosterinjections may be needed, for instance, at intervals of about two weeks,to provide a useful titer of anti-peptide antibody which can bedetected, for example, by ELISA assay using free peptide adsorbed to asolid surface. The titer of anti-peptide antibodies in serum from animmunized animal may be increased by selection of anti-peptideantibodies, for instance, by adsorption to the peptide on a solidsupport and elution of the selected antibodies according to methods wellknown in the art.

As one of skill in the art will appreciate, and as discussed above, thepolypeptides of the present invention (e.g., those comprising animmunogenic or antigenic epitope) can be fused to heterologouspolypeptide sequences. For example, polypeptides of the presentinvention (including fragments or variants thereof), may be fused withthe constant domain of immunoglobulins (IgA, IgE, IgG, IgM), or portionsthereof (CH1, CH2, CH3, or any combination thereof and portions thereof,resulting in chimeric polypeptides. By way of another non-limitingexample, polypeptides and/or antibodies of the present invention(including fragments or variants thereof) may be fused with albumin(including but not limited to recombinant human serum albumin orfragments or variants thereof (see, e.g., U.S. Pat. No. 5,876,969,issued Mar. 2, 1999, EP Patent 0 413 622, and U.S. Pat. No. 5,766,883,issued Jun. 16, 1998, herein incorporated by reference in theirentirety)). In a preferred embodiment, polypeptides and/or antibodies ofthe present invention (including fragments or variants thereof) arefused with the mature form of human serum albumin (i.e., amino acids1-585 of human serum albumin as shown in FIGS. 1 and 2 of EP Patent 0322 094) which is herein incorporated by reference in its entirety. Inanother preferred embodiment, polypeptides and/or antibodies of thepresent invention (including fragments or variants thereof) are fusedwith polypeptide fragments comprising, or alternatively consisting of,amino acid residues 1-z of human serum albumin, where z is an integerfrom 369 to 419, as described in U.S. Pat. No. 5,766,883 hereinincorporated by reference in its entirety. Polypeptides and/orantibodies of the present invention (including fragments or variantsthereof) may be fused to either the N- or C-terminal end of theheterologous protein (e.g., immunoglobulin Fc polypeptide or human serumalbumin polypeptide). Polynucleotides encoding fusion proteins of theinvention are also encompassed by the invention.

Such fusion proteins as those described above may facilitatepurification and may increase half-life in vivo. This has been shown forchimeric proteins consisting of the first two domains of the humanCD4-polypeptide and various domains of the constant regions of the heavyor light chains of mammalian immunoglobulins. See, e.g., EP 394,827;Traunecker et al., Nature, 331:84-86 (1988). Enhanced delivery of anantigen across the epithelial barrier to the immune system has beendemonstrated for antigens (e.g., insulin) conjugated to an FcRn bindingpartner such as IgG or Fc fragments (see, e.g., PCT Publications WO96/22024 and WO 99/04813). IgG fusion proteins that have adisulfide-linked dimeric structure due to the IgG portion desulfidebonds have also been found to be more efficient in binding andneutralizing other molecules than monomeric polypeptides or fragmentsthereof alone. See, e.g., Fountoulakis et al., J. Biochem.,270:3958-3964 (1995). Nucleic acids encoding the above epitopes can alsobe recombined with a gene of interest as an epitope tag (e.g., thehemagglutinin (HA) tag or flag tag) to aid in detection and purificationof the expressed polypeptide. For example, a system described byJanknecht et al. allows for the ready purification of non-denaturedfusion proteins expressed in human cell lines (Janknecht et al., 1991,Proc. Natl. Acad. Sci. USA 88:8972-897). In this system, the gene ofinterest is subcloned into a vaccinia recombination plasmid such thatthe open reading frame of the gene is translationally fused to anamino-terminal tag consisting of six histidine residues. The tag servesas a matrix binding domain for the fusion protein. Extracts from cellsinfected with the recombinant vaccinia virus are loaded onto Ni2+nitriloacetic acid-agarose column and histidine-tagged proteins can beselectively eluted with imidazole-containing buffers.

Fusion Proteins

Any polypeptide of the present invention can be used to generate fusionproteins. For example, the polypeptide of the present invention, whenfused to a second protein, can be used as an antigenic tag. Antibodiesraised against the polypeptide of the present invention can be used toindirectly detect the second protein by binding to the polypeptide.Moreover, because secreted proteins target cellular locations based ontrafficking signals, polypeptides of the present invention which areshown to be secreted can be used as targeting molecules once fused toother proteins.

Examples of domains that can be fused to polypeptides of the presentinvention include not only heterologous signal sequences, but also otherheterologous functional regions. The fusion does not necessarily need tobe direct, but may occur through linker sequences.

In certain preferred embodiments, proteins of the invention are fusionproteins comprising an amino acid sequence that is an N and/orC-terminal deletion of a polypeptide of the invention. In preferredembodiments, the invention is directed to a fusion protein comprising anamino acid sequence that is at least 90%, 95%, 96%, 97%, 98% or 99%identical to a polypeptide sequence of the invention. Polynucleotidesencoding these proteins are also encompassed by the invention.

Moreover, fusion proteins may also be engineered to improvecharacteristics of the polypeptide of the present invention. Forinstance, a region of additional amino acids, particularly charged aminoacids, may be added to the N-terminus of the polypeptide to improvestability and persistence during purification from the host cell orsubsequent handling and storage. Also, peptide moieties may be added tothe polypeptide to facilitate purification. Such regions may be removedprior to final preparation of the polypeptide. The addition of peptidemoieties to facilitate handling of polypeptides are familiar and routinetechniques in the art.

As one of skill in the art will appreciate that, as discussed above,polypeptides of the present invention, and epitope-bearing fragmentsthereof, can be combined with heterologous polypeptide sequences. Forexample, the polypeptides of the present invention may be fused withheterologous polypeptide sequences, for example, the polypeptides of thepresent invention may be fused with the constant domain ofimmunoglobulins (IgA, IgE, IgG, IgM) or portions thereof (CH1, CH2, CH3,and any combination thereof, including both entire domains and portionsthereof), or albumin (including, but not limited to, native orrecombinant human albumin or fragments or variants thereof (see, e.g.,U.S. Pat. No. 5,876,969, issued Mar. 2, 1999, EP Patent 0 413 622, andU.S. Pat. No. 5,766,883, issued Jun. 16, 1998, herein incorporated byreference in their entirety)), resulting in chimeric polypeptides. Forexample, EP-A-O 464 533 (Canadian counterpart 2045869) discloses fusionproteins comprising various portions of constant region ofimmunoglobulin molecules together with another human protein or partthereof. In many cases, the Fc part in a fusion protein is beneficial intherapy and diagnosis, and thus can result in, for example, improvedpharmacokinetic properties (EP-A 0232 262). Alternatively, deleting theFc part after the fusion protein has been expressed, detected, andpurified, would be desired. For example, the Fc portion may hindertherapy and diagnosis if the fusion protein is used as an antigen forimmunizations. In drug discovery, for example, human proteins, such ashIL-5, have been fused with Fc portions for the purpose ofhigh-throughput screening assays to identify antagonists of hIL-5. See,D. Bennett et al., J. Molecular Recognition 8:52-58 (1995); K. Johansonet al., J. Biol. Chem. 270:9459-9471 (1995).

Moreover, the polypeptides of the present invention can be fused tomarker sequences, such as a polypeptide which facilitates purificationof the fused polypeptide. In preferred embodiments, the marker aminoacid sequence is a hexa-histidine peptide, such as the tag provided in apQE vector (QIAGEN, Inc., 9259 Eton Avenue, Chatsworth, Calif., 91311),among others, many of which are commercially available. As described inGentz et al., Proc. Natl. Acad. Sci. USA 86:821-824 (1989), forinstance, hexa-histidine provides for convenient purification of thefusion protein. Another peptide tag useful for purification, the “HA”tag, corresponds to an epitope derived from the influenza hemagglutininprotein (Wilson et al., Cell 37:767 (1984)).

Additional fusion proteins of the invention may be generated through thetechniques of gene-shuffling, motif-shuffling, exon-shuffling, and/orcodon-shuffling (collectively referred to as “DNA shuffling”). DNAshuffling may be employed to modulate the activities of polypeptides ofthe invention, such methods can be used to generate polypeptides withaltered activity, as well as agonists and antagonists of thepolypeptides. See, generally, U.S. Pat. Nos. 5,605,793; 5,811,238;5,830,721; 5,834,252; and 5,837,458, and Patten et al., Curr. OpinionBiotechnol. 8:724-33 (1997); Harayama, Trends Biotechnol. 16(2):76-82(1998); Hansson, et al., J. Mol. Biol. 287:265-76 (1999); and Lorenzoand Blasco, Biotechniques 24(2):308-13 (1998) (each of these patents andpublications are hereby incorporated by reference in its entirety). Inone embodiment, alteration of polynucleotides corresponding to SEQ IDNO:X and the polypeptides encoded by these polynucleotides may beachieved by DNA shuffling. DNA shuffling involves the assembly of two ormore DNA segments by homologous or site-specific recombination togenerate variation in the polynucleotide sequence. In anotherembodiment, polynucleotides of the invention, or the encodedpolypeptides, may be altered by being subjected to random mutagenesis byerror-prone PCR, random nucleotide insertion or other methods prior torecombination. In another embodiment, one or more components, motifs,sections, parts, domains, fragments, etc., of a polynucleotide encodinga polypeptide of the invention may be recombined with one or morecomponents, motifs, sections, parts, domains, fragments, etc. of one ormore heterologous molecules.

Thus, any of these above fusions can be engineered using thepolynucleotides or the polypeptides of the present invention.

Recombinant and Synthetic Production of Polypeptides of the Invention

The present invention also relates to vectors containing thepolynucleotide of the present invention, host cells, and the productionof polypeptides by synthetic and recombinant techniques. The vector maybe, for example, a phage, plasmid, viral, or retroviral vector.Retroviral vectors may be replication competent or replicationdefective. In the latter case, viral propagation generally will occuronly in complementing host cells.

The polynucleotides of the invention may be joined to a vectorcontaining a selectable marker for propagation in a host. Generally, aplasmid vector is introduced in a precipitate, such as a calciumphosphate precipitate, or in a complex with a charged lipid. If thevector is a virus, it may be packaged in vitro using an appropriatepackaging cell line and then transduced into host cells.

The polynucleotide insert should be operatively linked to an appropriatepromoter, such as the phage lambda PL promoter, the E. coli lac, trp,phoA and tac promoters, the SV40 early and late promoters and promotersof retroviral LTRs, to name a few. Other suitable promoters will beknown to the skilled artisan. The expression constructs will furthercontain sites for transcription initiation, termination, and, in thetranscribed region, a ribosome binding site for translation. The codingportion of the transcripts expressed by the constructs will preferablyinclude a translation initiating codon at the beginning and atermination codon (UAA, UGA or UAG) appropriately positioned at the endof the polypeptide to be translated.

As indicated, the expression vectors will preferably include at leastone selectable marker. Such markers include dihydrofolate reductase,G418, glutamine synthase, or neomycin resistance for eukaryotic cellculture, and tetracycline, kanamycin or ampicillin resistance genes forculturing in E. coli and other bacteria. Representative examples ofappropriate hosts include, but are not limited to, bacterial cells, suchas E. coli, Streptomyces and Salmonella typhimurium cells; fungal cells,such as yeast cells (e.g., Saccharomyces cerevisiae or Pichia pastoris(ATCC Accession No. 201178)); insect cells such as Drosophila S2 andSpodoptera Sf9 cells; animal cells such as CHO, COS, 293, and Bowesmelanoma cells; and plant cells. Appropriate culture mediums andconditions for the above-described host cells are known in the art.

Among vectors preferred for use in bacteria include pQE70, pQE60 andpQE-9, available from QIAGEN, Inc.; pBluescript vectors, Phagescriptvectors, pNH8A, pNH16a, pNH18A, pNH46A, available from StratageneCloning Systems, Inc.; and ptrc99a, pKK223-3, pKK233-3, pDR540, pRIT5available from Pharmacia Biotech, Inc. Among preferred eukaryoticvectors are pWLNEO, pSV2CAT, pOG44, pXT1 and pSG available fromStratagene; and pSVK3, pBPV, pMSG and pSVL available from Pharmacia.Preferred expression vectors for use in yeast systems include, but arenot limited to pYES2, pYD1, pTEF1/Zeo, pYES2/GS, pPICZ, pGAPZ,pGAPZalph, pPIC9, pPIC3.5, pHIL-D2, pHIL-S1, pPIC3.5K, pPIC9K, andPAO815 (all available from Invitrogen, Carlbad, Calif.). Other suitablevectors will be readily apparent to the skilled artisan.

Vectors which use glutamine synthase (GS) or DHFR as the selectablemarkers can be amplified in the presence of the drugs methioninesulphoximine or methotrexate, respectively. An advantage of glutaminesynthase based vectors are the availabilty of cell lines (e.g., themurine myeloma cell line, NS0) which are glutamine synthase negative.Glutamine synthase expression systems can also function in glutaminesynthase expressing cells (e.g., Chinese Hamster Ovary (CHO) cells) byproviding additional inhibitor to prevent the functioning of theendogenous gene. A glutamine synthase expression system and componentsthereof are detailed in PCT publications: WO87/04462; WO86/05807;WO89/01036; WO89/10404; and WO91/06657, which are hereby incorporated intheir entireties by reference herein. Additionally, glutamine synthaseexpression vectors can be obtained from Lonza Biologics, Inc.(Portsmouth, N.H.). Expression and production of monoclonal antibodiesusing a GS expression system in murine myeloma cells is described inBebbington et al., Bio/technology 10:169(1992) and in Biblia andRobinson Biotechnol. Prog. 11:1 (1995) which are herein incorporated byreference.

The present invention also relates to host cells containing theabove-described vector constructs described herein, and additionallyencompasses host cells containing nucleotide sequences of the inventionthat are operably associated with one or more heterologous controlregions (e.g., promoter and/or enhancer) using techniques known of inthe art. The host cell can be a higher eukaryotic cell, such as amammalian cell (e.g., a human derived cell), or a lower eukaryotic cell,such as a yeast cell, or the host cell can be a prokaryotic cell, suchas a bacterial cell. A host strain may be chosen which modulates theexpression of the inserted gene sequences, or modifies and processes thegene product in the specific fashion desired. Expression from certainpromoters can be elevated in the presence of certain inducers; thusexpression of the genetically engineered polypeptide may be controlled.Furthermore, different host cells have characteristics and specificmechanisms for the translational and post-translational processing andmodification (e.g., phosphorylation, cleavage) of proteins. Appropriatecell lines can be chosen to ensure the desired modifications andprocessing of the foreign protein expressed.

Introduction of the nucleic acids and nucleic acid constructs of theinvention into the host cell can be effected by calcium phosphatetransfection, DEAE-dextran mediated transfection, cationiclipid-mediated transfection, electroporation, transduction, infection,or other methods. Such methods are described in many standard laboratorymanuals, such as Davis et al., Basic Methods In Molecular Biology(1986). It is specifically contemplated that the polypeptides of thepresent invention may in fact be expressed by a host cell lacking arecombinant vector.

In addition to encompassing host cells containing the vector constructsdiscussed herein, the invention also encompasses primary, secondary, andimmortalized host cells of vertebrate origin, particularly mammalianorigin, that have been engineered to delete or replace endogenousgenetic material (e.g., the coding sequence), and/or to include geneticmaterial (e.g., heterologous polynucleotide sequences) that is operablyassociated with polynucleotides of the invention, and which activates,alters, and/or amplifies endogenous polynucleotides. For example,techniques known in the art may be used to operably associateheterologous control regions (e.g., promoter and/or enhancer) andendogenous polynucleotide sequences via homologous recombination (see,e.g., U.S. Pat. No. 5,641,670, issued Jun. 24, 1997; InternationalPublication Number WO 96/29411; International Publication Number WO94/12650; Koller et al., Proc. Natl. Acad. Sci. USA 86:8932-8935 (1989);and Zijlstra et al., Nature 342:435-438 (1989), the disclosures of eachof which are incorporated by reference in their entireties).

Polypeptides of the invention can be recovered and purified fromrecombinant cell cultures by well-known methods including ammoniumsulfate or ethanol precipitation, acid extraction, anion or cationexchange chromatography, phosphocellulose chromatography, hydrophobicinteraction chromatography, affinity chromatography, hydroxylapatitechromatography and lectin chromatography. Most preferably, highperformance liquid chromatography (“HPLC”) is employed for purification.

Polypeptides of the present invention can also be recovered from:products purified from natural sources, including bodily fluids, tissuesand cells, whether directly isolated or cultured; products of chemicalsynthetic procedures; and products produced by recombinant techniquesfrom a prokaryotic or eukaryotic host, including, for example,bacterial, yeast, higher plant, insect, and mammalian cells. Dependingupon the host employed in a recombinant production procedure, thepolypeptides of the present invention may be glycosylated or may benon-glycosylated. In addition, polypeptides of the invention may alsoinclude an initial modified methionine residue, in some cases as aresult of host-mediated processes. Thus, it is well known in the artthat the N-terminal methionine encoded by the translation initiationcodon generally is removed with high efficiency from any protein aftertranslation in all eukaryotic cells. While the N-terminal methionine onmost proteins also is efficiently removed in most prokaryotes, for someproteins, this prokaryotic removal process is inefficient, depending onthe nature of the amino acid to which the N-terminal methionine iscovalently linked.

In one embodiment, the yeast Pichia pastoris is used to expresspolypeptides of the invention in a eukaryotic system Pichia pastoris isa methylotrophic yeast which can metabolize methanol as its sole carbonsource. A main step in the methanol metabolization pathway is theoxidation of methanol to formaldehyde using O₂. This reaction iscatalyzed by the enzyme alcohol oxidase. In order to metabolize methanolas its sole carbon source, Pichia pastoris must generate high levels ofalcohol oxidase due, in part, to the relatively low affinity of alcoholoxidase for O₂-Consequently, in a growth medium depending on methanol asa main carbon source, the promoter region of one of the two alcoholoxidase genes (AOXI) is highly active. In the presence of methanol,alcohol oxidase produced from the AOXI gene comprises up toapproximately 30% of the total soluble protein in Pichia pastoris. SeeEllis, S. B., et al., Mol. Cell. Biol. 5:1111-21 (1985); Koutz, P. J, etal., Yeast 5:167-77 (1989); Tschopp, J. F., et al., Nucl. Acids Res.15:3859-76 (1987). Thus, a heterologous coding sequence, such as, forexample, a polynucleotide of the present invention, under thetranscriptional regulation of all or part of the AOXI regulatorysequence is expressed at exceptionally high levels in Pichia yeast grownin the presence of methanol.

In one example, the plasmid vector pPIC9K is used to express DNAencoding a polypeptide of the invention, as set forth herein, in aPichea yeast system essentially as described in “Pichia Protocols:Methods in Molecular Biology,” D. R. Higgins and J. Cregg, eds. TheHumana Press, Totowa, N.J., 1998. This expression vector allowsexpression and secretion of a polypeptide of the invention by virtue ofthe strong AOXI promoter linked to the Pichia pastoris alkalinephosphatase (PHO) secretory signal peptide (i.e., leader) locatedupstream of a multiple cloning site.

Many other yeast vectors could be used in place of pPIC9K, such as,pYES2, pYD1, pThF1/Zeo, pYES2/GS, pPICZ, pGAPZ, pGAPZalpha, pPIC9,pPIC3.5, pHIL-D2, pHIL-S1, pPIC3.5K, and PAO815, as one skilled in theart would readily appreciate, as long as the proposed expressionconstruct provides appropriately located signals for transcription,translation, secretion (if desired), and the like, including an in-frameAUG as required.

In another embodiment, high-level expression of a heterologous codingsequence, such as, for example, a polynucleotide of the presentinvention, may be achieved by cloning the heterologous polynucleotide ofthe invention into an expression vector such as, for example, pGAPZ orpGAPZalpha, and growing the yeast culture in the absence of methanol.

In addition to encompassing host cells containing the vector constructsdiscussed herein, the invention also encompasses primary, secondary, andimmortalized host cells of vertebrate origin, particularly mammalianorigin, that have been engineered to delete or replace endogenousgenetic material (e.g., coding sequence), and/or to include geneticmaterial (e.g., heterologous polynucleotide sequences) that is operablyassociated with polynucleotides of the invention, and which activates,alters, and/or amplifies endogenous polynucleotides. For example,techniques known in the art may be used to operably associateheterologous control regions (e.g., promoter and/or enhancer) andendogenous polynucleotide sequences via homologous recombination (see,e.g., U.S. Pat. No. 5,641,670, issued Jun. 24, 1997; InternationalPublication No. WO 96/29411, published Sep. 26, 1996; InternationalPublication No. WO 94/12650, published Aug. 4, 1994; Koller et al.,Proc. Natl. Acad. Sci. USA 86:8932-8935 (1989); and Zijlstra et al.,Nature 342:435438 (1989), the disclosures of each of which areincorporated by reference in their entireties).

In addition, polypeptides of the invention can be chemically synthesizedusing techniques known in the art (e.g., see Creighton, 1983, Proteins:Structures and Molecular Principles, W.H. Freeman & Co., N.Y., andHunkapiller et al., Nature, 310:105-111 (1984)). For example, apolypeptide corresponding to a fragment of a polypeptide can besynthesized by use of a peptide synthesizer. Furthermore, if desired,nonclassical amino acids or chemical amino acid analogs can beintroduced as a substitution or addition into the polypeptide sequence.Non-classical amino acids include, but are not limited to, to theD-isomers of the common amino acids, 2,4-diaminobutyric acid, a-aminoisobutyric acid, 4-aminobutyric acid, Abu, 2-amino butyric acid, g-Abu,e-Ahx, 6-amino hexanoic acid, Aib, 2-amino isobutyric acid, 3-aminopropionic acid, ornithine, norleucine, norvaline, hydroxyproline,sarcosine, citrulline, homocitrulline, cysteic acid, t-butylglycine,t-butylalanine, phenylglycine, cyclohexylalanine, b-alanine,fluoro-amino acids, designer amino acids such as b-methyl amino acids,Ca-methyl amino acids, Na-methyl amino acids, and amino acid analogs ingeneral. Furthermore, the amino acid can be D (dextrorotary) or L(levorotary).

The invention encompasses polypeptides of the present invention whichare differentially modified during or after translation, e.g., byglycosylation, acetylation, phosphorylation, amidation, derivatizationby known protecting/blocking groups, proteolytic cleavage, linkage to anantibody molecule or other cellular ligand, etc. Any of numerouschemical modifications may be carried out by known techniques, includingbut not limited, to specific chemical cleavage by cyanogen bromide,trypsin, chymotrypsin, papain, V8 protease, NaBH₄; acetylation,formylation, oxidation, reduction; metabolic synthesis in the presenceof tunicamycin; etc.

Additional post-translational modifications encompassed by the inventioninclude, for example, e.g., N-linked or O-linked carbohydrate chains,processing of N-terminal or C-terminal ends), attachment of chemicalmoieties to the amino acid backbone, chemical modifications of N-linkedor O-linked carbohydrate chains, and addition or deletion of anN-terminal methionine residue as a result of procaryotic host cellexpression. The polypeptides may also be modified with a detectablelabel, such as an enzymatic, fluorescent, isotopic or affinity label toallow for detection and isolation of the protein.

Examples of suitable enzymes include horseradish peroxidase, alkalinephosphatase, beta-galactosidase, or acetylcholinesterase; examples ofsuitable prosthetic group complexes include streptavidin/biotin andavidin/biotin; examples of suitable fluorescent materials includeumbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine,dichlorotriazinylamine fluorescein, dansyl chloride dr phycoerythrin; anexample of a luminescent material includes luminol; examples ofbioluminescent materials include luciferase, luciferin, and aequorin;and examples of suitable radioactive material include iodine (¹²¹I,¹²³I, ¹²⁵I, ¹³¹I), carbon (¹⁴C), sulfur (³⁵S), tritium (³H) indium(¹¹¹In, ¹¹²In, ^(113m)In, ^(115m)In), technetium (⁹⁹Tc, ^(99m)Tc),thallium (²⁰¹Ti), gallium (⁶⁸Ga, ⁶⁷Ga), palladium (¹⁰³Pd), molybdenum(⁹⁹Mo), xenon (¹³³Xe), fluorine (¹⁸F), ¹⁵³Sm, ¹⁷⁷Lu, ¹⁵⁹Gd, ¹⁴⁹ Pm,¹⁴⁰La, ¹⁷⁵Yb, ¹⁶⁶Ho, ⁹⁰Y, ⁴⁷Sc, ¹⁸⁶Re, ¹⁸⁸Re, ¹⁴²Pr, ¹⁰⁵Rh, and ⁹⁷RU.

In specific embodiments, a polypeptide of the present invention orfragment or variant thereof is attached to macrocyclic chelators thatassociate with radiometal ions, including but not limited to, ¹⁷⁷Lu,⁹⁰Y, ¹⁶⁶Ho, and ¹⁵³Sm, to polypeptides. In a preferred embodiment, theradiometal ion associated with the macrocyclic chelators is ¹¹¹In. Inanother preferred embodiment, the radiometal ion associated with themacrocyclic chelator is ⁹⁰Y. In specific embodiments, the macrocyclicchelator is 1,4,7,10-tetraazacyclododecane-N,N′,N″,N′″-tetraacetic acid(DOTA). In other specific embodiments, DOTA is attached to an antibodyof the invention or fragment thereof via a linker molecule. Examples oflinker molecules useful for conjugating DOTA to a polypeptide arecommonly known in the art—see, for example, DeNardo et al., Clin CancerRes. 4(10):2483-90 (1998); Peterson et al., Bioconjug. Chem. 10(4):553-7(1999); and Zimmerman et al, Nucl. Med. Biol. 26(8):943-50 (1999); whichare hereby incorporated by reference in their entirety.

As mentioned, the proteins of the invention may be modified by eithernatural processes, such as posttranslational processing, or by chemicalmodification techniques which are well known in the art. It will beappreciated that the same type of modification may be present in thesame or varying degrees at several sites in a given polypeptide.Polypeptides of the invention may be branched, for example, as a resultof ubiquitination, and they may be cyclic, with or without branching.Cyclic, branched, and branched cyclic polypeptides may result fromposttranslation natural processes or may be made by synthetic methods.Modifications include acetylation, acylation, ADP-ribosylation,amidation, covalent attachment of flavin, covalent attachment of a hememoiety, covalent attachment of a nucleotide or nucleotide derivative,covalent attachment of a lipid or lipid derivative, covalent attachmentof phosphotidylinositol, cross-linking, cyclization, disulfide bondformation, demethylation, formation of covalent cross-links, formationof cysteine, formation of pyroglutamate, formylation,gamma-carboxylation, glycosylation, GPI anchor formation, hydroxylation,iodination, methylation, myristoylation, oxidation, pegylation,proteolytic processing, phosphorylation, prenylation, racemization,selenoylation, sulfation, transfer-RNA mediated addition of amino acidsto proteins such as arginylation, and ubiquitination. (See, forinstance, PROTEINS—STRUCTURE AND MOLECULAR PROPERTIES, 2nd Ed., T. E.Creighton, W. H. Freeman and Company, New York (1993); POSTTRANSLATIONALCOVALENT MODIFICATION OF PROTEINS, B. C. Johnson, Ed., Academic Press,New York, pgs. 1-12 (1983); Seifter et al., Meth. Enzymol. 182:626-646(1990); Rattan et al., Ann. N.Y. Acad. Sci. 663:48-62 (1992)).

Also provided by the invention are chemically modified derivatives ofthe polypeptides of the invention which may provide additionaladvantages such as increased solubility, stability and circulating timeof the polypeptide, or decreased immunogenicity (see U.S. Pat. No.4,179,337). The chemical moieties for derivitization may be selectedfrom water soluble polymers such as polyethylene glycol, ethyleneglycol/propylene glycol copolymers, carboxymethylcellulose, dextran,polyvinyl alcohol and the like. The polypeptides may be modified atrandom positions within the molecule, or at predetermined positionswithin the molecule and may include one, two, three or more attachedchemical moieties.

The polymer may be of any molecular weight, and may be branched orunbranched. For polyethylene glycol, the preferred molecular weight isbetween about 1 kDa and about 100 kDa (the term “about” indicating thatin preparations of polyethylene glycol, some molecules will weigh more,some less, than the stated molecular weight) for ease in handling andmanufacturing. Other sizes may be used, depending on the desiredtherapeutic profile (e.g., the duration of sustained release desired,the effects, if any on biological activity, the ease in handling, thedegree or lack of antigenicity and other known effects of thepolyethylene glycol to a therapeutic protein or analog). For example,the polyethylene glycol may have an average molecular weight of about200, 500, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 5500,6000, 6500, 7000, 7500, 8000, 8500, 9000, 9500, 10,000, 10,500, 11,000,11,500, 12,000, 12,500, 13,000, 13,500, 14,000, 14,500, 15,000, 15,500,16,000, 16,500, 17,000, 17,500, 18,000, 18,500, 19,000, 19,500, 20,000,25,000, 30,000, 35,000, 40,000, 45,000, 50,000, 55,000, 60,000, 65,000,70,000, 75,000, 80,000, 85,000, 90,000, 95,000, or 100,000 kDa.

As noted above, the polyethylene glycol may have a branched structure.Branched polyethylene glycols are described, for example, in U.S. Pat.No. 5,643,575; Morpurgo et al., Appl. Biochem Biotechnol. 56:59-72(1996); Vorobjev et al., Nucleosides Nucleotides 18:2745-2750 (1999);and Caliceti et al., Bioconjug. Chem. 10:638-646 (1999), the disclosuresof each of which are incorporated herein by reference.

The polyethylene glycol molecules (or other chemical moieties) should beattached to the protein with consideration of effects on functional orantigenic domains of the protein. There are a number of attachmentmethods available to those skilled in the art, such as, for example, themethod disclosed in EP 0 401 384 (coupling PEG to G-CSF), hereinincorporated by reference; see also Malik et al., Exp. Hematol.20:1028-1035 (1992), reporting pegylation of GM-CSF using tresylchloride. For example, polyethylene glycol may be covalently boundthrough amino acid residues via a reactive group, such as a free aminoor carboxyl group. Reactive groups are those to which an activatedpolyethylene glycol molecule may be bound. The amino acid residueshaving a free amino group may include lysine residues and the N-terminalamino acid residues; those having a free carboxyl group may includeaspartic acid residues glutamic acid residues and the C-terminal aminoacid residue. Sulfhydryl groups may also be used as a reactive group forattaching the polyethylene glycol molecules. Preferred for therapeuticpurposes is attachment at an amino group, such as attachment at theN-terminus or lysine group.

As suggested above, polyethylene glycol may be attached to proteins vialinkage to any of a number of amino acid residues. For example,polyethylene glycol can be linked to proteins via covalent bonds tolysine, histidine, aspartic acid, glutamic acid, or cysteine residues.One or more reaction chemistries may be employed to attach polyethyleneglycol to specific amino acid residues (e.g., lysine, histidine,aspartic acid, glutamic acid, or cysteine) of the protein or to morethan one type of amino acid residue (e.g., lysine, histidine, asparticacid, glutamic acid, cysteine and combinations thereof) of the protein.

One may specifically desire proteins chemically modified at theN-terminus. Using polyethylene glycol as an illustration of the presentcomposition, one may select from a variety of polyethylene glycolmolecules (by molecular weight, branching, etc.), the proportion ofpolyethylene glycol molecules to protein (polypeptide) molecules in thereaction mix, the type of pegylation reaction to be performed, and themethod of obtaining the selected N-terminally pegylated protein. Themethod of obtaining the N-terminally pegylated preparation (i.e.,separating this moiety from other monopegylated moieties if necessary)may be by purification of the N-terminally pegylated material from apopulation of pegylated protein molecules. Selective proteins chemicallymodified at the N-terminus modification may be accomplished by reductivealkylation which exploits differential reactivity of different types ofprimary amino groups (lysine versus the N-terminal) available forderivatization in a particular protein. Under the appropriate reactionconditions, substantially selective derivatization of the protein at theN-terminus with a carbonyl group containing polymer is achieved.

As indicated above, pegylation of the proteins of the invention may beaccomplished by any number of means. For example, polyethylene glycolmay be attached to the protein either directly or by an interveninglinker. Linkerless systems for attaching polyethylene glycol to proteinsare described in Delgado et al., Crit. Rev. Thera. Drug Carrier Sys.9:249-304 (1992); Francis et al., Intern. J. of Hematol. 68:1-18 (1998);U.S. Pat. No. 4,002,531; U.S. Pat. No. 5,349,052; WO 95/06058; and WO98/32466, the disclosures of each of which are incorporated herein byreference.

One system for attaching polyethylene glycol directly to amino acidresidues of proteins without an intervening linker employs tresylatedMPEG, which is produced by the modification of monmethoxy polyethyleneglycol (MPEG) using tresylchloride (ClSO₂CH₂CF₃). Upon reaction ofprotein with tresylated MPEG, polyethylene glycol is directly attachedto amine groups of the protein. Thus, the invention includesprotein-polyethylene glycol conjugates produced by reacting proteins ofthe invention with a polyethylene glycol molecule having a2,2,2-trifluoreothane sulphonyl group.

Polyethylene glycol can also be attached to proteins using a number ofdifferent intervening linkers. For example, U.S. Pat. No. 5,612,460, theentire disclosure of which is incorporated herein by reference,discloses urethane linkers for connecting polyethylene glycol toproteins. Protein-polyethylene glycol conjugates wherein thepolyethylene glycol is attached to the protein by a linker can also beproduced by reaction of proteins with compounds such asMPEG-succininidylsuccinate, MPEG activated with1,1′-carbonyldiinudazole, MPEG-2,4,5-trichloropenylcarbonate,MPEG-p-nitrophenolcarbonate, and various MPEG-succinate derivatives. Anumber of additional polyethylene glycol derivatives and reactionchemistries for attaching polyethylene glycol to proteins are describedin International Publication No. WO 98/32466, the entire disclosure ofwhich is incorporated herein by reference. Pegylated protein productsproduced using the reaction chemistries set out herein are includedwithin the scope of the invention.

The number of polyethylene glycol moieties attached to each protein ofthe invention (i.e., the degree of substitution) may also vary. Forexample, the pegylated proteins of the invention may be linked, onaverage, to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, 17, 20, or morepolyethylene glycol molecules. Similarly, the average degree ofsubstitution within ranges such as 1-3,2-4, 3-5,4-6, 5-7,6-8, 7-9,8-10,9-11, 10-12, 11-13, 12-14, 13-15, 14-16, 15-17, 16-18, 17-19, or 18-20polyethylene glycol moieties per protein molecule. Methods fordetermining the degree of substitution are discussed, for example, inDelgado et al., Crit. Rev. Thera. Drug Carrier Sys. 9:249-304 (1992).

The polypeptides of the invention can be recovered and purified fromchemical synthesis and recombinant cell cultures by standard methodswhich include, but are not limited to, ammonium sulfate or ethanolprecipitation, acid extraction, anion or cation exchange chromatography,phosphocellulose chromatography, hydrophobic interaction chromatography,affinity chromatography, hydroxylapatite chromatography and lectinchromatography. Most preferably, high performance liquid chromatography(“HPLC”) is employed for purification. Well known techniques forrefolding protein may be employed to regenerate active conformation whenthe polypeptide is denatured during isolation and/or purification.

The polypeptides of the invention may be in monomers or multimers (i.e.,dimers, trimers, tetramers and higher multimers). Accordingly, thepresent invention relates to monomers and multimers of the polypeptidesof the invention, their preparation, and compositions (preferably,Therapeutics) containing them. In specific embodiments, the polypeptidesof the invention are monomers, dimers, trimers or tetramers. Inadditional embodiments, the multimers of the invention are at leastdimers, at least trimers, or at least tetramers.

Multimers encompassed by the invention may be homomers or heteromers. Asused herein, the term homomer refers to a multimer containing onlypolypeptides corresponding to a protein of the invention (e.g., theamino acid sequence of SEQ ID NO:Y, an amino acid sequence encoded bySEQ ID NO:X or the complement of SEQ ID NO:X, the amino acid sequenceencoded by the portion of SEQ ID NO:X as defined in columns 8 and 9 ofTable 2, and/or an amino acid sequence encoded by cDNA contained in ATCCDeposit No:Z (including fragments, variants, splice variants, and fusionproteins, corresponding to these as described herein)). These homomersmay contain polypeptides having identical or different amino acidsequences. In a specific embodiment, a homomer of the invention is amultimer containing only polypeptides having an identical amino acidsequence. In another specific embodiment, a homomer of the invention isa multimer containing polypeptides having different amino acidsequences. In specific embodiments, the multimer of the invention is ahomodimer (e.g., containing two polypeptides having identical ordifferent amino acid sequences) or a homotrimer (e.g., containing threepolypeptides having identical and/or different amino acid sequences). Inadditional embodiments, the homomeric multimer of the invention is atleast a homodimer, at least a homotrimer, or at least a homotetramer.

As used herein, the term heteromer refers to a multimer containing oneor more heterologous polypeptides (i.e., polypeptides of differentproteins) in addition to the polypeptides of the invention. In aspecific embodiment, the multimer of the invention is a heterodimer, aheterotrimer, or a heterotetramer. In additional embodiments, theheteromeric multimer of the invention is at least a heterodimer, atleast a heterotrimer, or at least a heterotetramer.

Multimers of the invention may be the result of hydrophobic,hydrophilic, ionic and/or covalent associations and/or may be indirectlylinked by, for example, liposome formation. Thus, in one embodiment,multimers of the invention, such as, for example, homodimers orhomotrimers, are formed when polypeptides of the invention contact oneanother in solution. In another embodiment, heteromultimers of theinvention, such as, for example, heterotrimers or heterotetramers, areformed when polypeptides of the invention contact antibodies to thepolypeptides of the invention (including antibodies to the heterologouspolypeptide sequence in a fusion protein of the invention) in solution.In other embodiments, multimers of the invention are formed by covalentassociations with and/or between the polypeptides of the invention. Suchcovalent associations may involve one or more amino acid residuescontained in the polypeptide sequence (e.g., that recited in SEQ IDNO:Y, encoded by the portion of SEQ ID NO:X as defined in columns 8 and9 of Table 2, and/or encoded by the cDNA contained in ATCC DepositNo:Z). In one instance, the covalent associations are cross-linkingbetween cysteine residues located within the polypeptide sequences whichinteract in the native (i.e., naturally occurring) polypeptide. Inanother instance, the covalent associations are the consequence ofchemical or recombinant manipulation. Alternatively, such covalentassociations may involve one or more amino acid residues contained inthe heterologous polypeptide sequence in a fusion protein. In oneexample, covalent associations are between the heterologous sequencecontained in a fusion protein of the invention (see, e.g., U.S. Pat. No.5,478,925). In a specific example, the covalent associations are betweenthe heterologous sequence contained in a Fc fusion protein of theinvention (as described herein). In another specific example, covalentassociations of fusion proteins of the invention are betweenheterologous polypeptide sequence from another protein that is capableof forming covalently associated multimers, such as for example,osteoprotegerin (see, e.g., International Publication NO: WO 98/49305,the contents of which are herein incorporated by reference in itsentirety). In another embodiment, two or more polypeptides of theinvention are joined through peptide linkers. Examples include thosepeptide linkers described in U.S. Pat. No. 5,073,627 (herebyincorporated by reference). Proteins comprising multiple polypeptides ofthe invention separated by peptide linkers may be produced usingconventional recombinant DNA technology.

Another method for preparing multimer polypeptides of the inventioninvolves use of polypeptides of the invention fused to a leucine zipperor isoleucine zipper polypeptide sequence. Leucine zipper and isoleucinezipper domains are polypeptides that promote multimerization of theproteins in which they are found. Leucine zippers were originallyidentified in several DNA-binding proteins (Landschulz et al., Science240:1759, (1988)), and have since been found in a variety of differentproteins. Among the known leucine zippers are naturally occurringpeptides and derivatives thereof that dimerize or trimerize. Examples ofleucine zipper domains suitable for producing soluble multimericproteins of the invention are those described in PCT application WO94/10308, hereby incorporated by reference. Recombinant fusion proteinscomprising a polypeptide of the invention fused to a polypeptidesequence that dimerizes or trimerizes in solution are expressed insuitable host cells, and the resulting soluble multimeric fusion proteinis recovered from the culture supernatant using techniques known in theart.

Trimeric polypeptides of the invention may offer the advantage ofenhanced biological activity. Preferred leucine zipper moieties andisoleucine moieties are those that preferentially form trimers. Oneexample is a leucine zipper derived from lung surfactant protein D(SPD), as described in Hoppe et al. (FEBS Letters 344:191, (1994)) andin U.S. patent application Ser. No. 08/446,922, hereby incorporated byreference. Other peptides derived from naturally occurring trimericproteins may be employed in preparing trimeric polypeptides of theinvention.

In another example, proteins of the invention are associated byinteractions between Flag® polypeptide sequence contained in fusionproteins of the invention containing Flag® polypeptide sequence. In afurther embodiment, proteins of the invention are associated byinteractions between heterologous polypeptide sequence contained inFlag® fusion proteins of the invention and anti-Flag® antibody.

The multimers of the invention may be generated using chemicaltechniques known in the art. For example, polypeptides desired to becontained in the multimers of the invention may be chemicallycross-linked using linker molecules and linker molecule lengthoptimization techniques known in the art (see, e.g., U.S. Pat. No.5,478,925, which is herein incorporated by reference in its entirety).Additionally, multimers of the invention may be generated usingtechniques known in the art to form one or more inter-moleculecross-links between the cysteine residues located within the sequence ofthe polypeptides desired to be contained in the multimer (see, e.g.,U.S. Pat. No. 5,478,925, which is herein incorporated by reference inits entirety). Further, polypeptides of the invention may be routinelymodified by the addition of cysteine or biotin to the C-terminus orN-terminus of the polypeptide and techniques known in the art may beapplied to generate multimers containing one or more of these modifiedpolypeptides (see, e.g., U.S. Pat. No. 5,478,925, which is hereinincorporated by reference in its entirety). Additionally, techniquesknown in the art may be applied to generate liposomes containing thepolypeptide components desired to be contained in the multimer of theinvention (see, e.g., U.S. Pat. No. 5,478,925, which is hereinincorporated by reference in its entirety).

Alternatively, multimers of the invention may be generated using geneticengineering techniques known in the art. In one embodiment, polypeptidescontained in multimers of the invention are produced recombinantly usingfusion protein technology described herein or otherwise known in the art(see, e.g., U.S. Pat. No. 5,478,925, which is herein incorporated byreference in its entirety). In a specific embodiment, polynucleotidescoding for a homodimer of the invention are generated by ligating apolynucleotide sequence encoding a polypeptide of the invention to asequence encoding a linker polypeptide and then further to a syntheticpolynucleotide encoding the translated product of the polypeptide in thereverse orientation from the original C-terminus to the N-terminus(lacking the leader sequence) (see, e.g., U.S. Pat. No. 5,478,925, whichis herein incorporated by reference in its entirety). In anotherembodiment, recombinant techniques described herein or otherwise knownin the art are applied to generate recombinant polypeptides of theinvention which contain a transmembrane domain (or hydrophobic or signalpeptide) and which can be incorporated by membrane reconstitutiontechniques into liposomes (see, e.g., U.S. Pat. No. 5,478,925, which isherein incorporated by reference in its entirety).

Antibodies

Further polypeptides of the invention relate to antibodies and T-cellantigen receptors (TCR) which immunospecifically bind a polypeptide,polypeptide fragment, or variant of the invention (e.g., a polypeptideor fragment or variant of the amino acid sequence of SEQ ID NO:Y or apolypeptide encoded by the cDNA contained in ATCC Deposit No:Z, and/oran epitope, of the present invention) as determined by immunoassays wellknown in the art for assaying specific antibody-antigen binding.Antibodies of the invention include, but are not limited to, polyclonal,monoclonal, multispecific, human, humanized or chimeric antibodies,single chain antibodies, Fab fragments, F(ab′) fragments, fragmentsproduced by a Fab expression library, anti-idiotypic (anti-Id)antibodies (including, e.g., anti-Id antibodies to antibodies of theinvention), intracellularly-made antibodies (i.e., intrabodies), andepitope-binding fragments of any of the above. The term “antibody,” asused herein, refers to immunoglobulin molecules and immunologicallyactive portions of immunoglobulin molecules, i.e., molecules thatcontain an antigen binding site that immunospecifically binds anantigen. The immunoglobulin molecules of the invention can be of anytype (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgG1, IgG2,IgG3, IgG4, IgA1 and IgA2) or subclass of immunoglobulin molecule. Inpreferred embodiments, the immunoglobulin molecules of the invention areIgG1. In other preferred embodiments, the immunoglobulin molecules ofthe invention are IgG4.

Most preferably the antibodies are human antigen-binding antibodyfragments of the present invention and include, but are not limited to,Fab, Fab′ and F(ab′)2, Fd, single-chain Fvs (scFv), single-chainantibodies, disulfide-linked Fvs (sdFv) and fragments comprising eithera VL or VH domain. Antigen-binding antibody fragments, includingsingle-chain antibodies, may comprise the variable region(s) alone or incombination with the entirety or a portion of the following: hingeregion, CH1, CH2, and CH3 domains. Also included in the invention areantigen-binding fragments also comprising any combination of variableregion(s) with a hinge region, CH1, CH2, and CH3 domains. The antibodiesof the invention may be from any animal origin including birds andmammals. Preferably, the antibodies are human, murine (e.g., mouse andrat), donkey, ship rabbit, goat, guinea pig, camel, horse, or chicken.As used herein, “human” antibodies include antibodies having the aminoacid sequence of a human immunoglobulin and include antibodies isolatedfrom human immunoglobulin libraries or from animals transgenic for oneor more human immunoglobulin and that do not express endogenousimmunoglobulins, as described infra and, for example in, U.S. Pat. No.5,939,598 by Kucherlapati et al.

The antibodies of the present invention may be monospecific, bispecific,trispecific or of greater multispecificity. Multispecific antibodies maybe specific for different epitopes of a polypeptide of the presentinvention or may be specific for both a polypeptide of the presentinvention as well as for a heterologous epitope, such as a heterologouspolypeptide or solid support material. See, e.g., PCT publications WO93/17715; WO 92/08802; WO 91/00360; WO 92/05793; Tutt, et al., J.Immunol. 147:60-69 (1991); U.S. Pat. Nos. 4,474,893; 4,714,681;4,925,648; 5,573,920; 5,601,819; Kostelny et al., J. Immunol.148:1547-1553 (1992).

Antibodies of the present invention may be described or specified interms of the epitope(s) or portion(s) of a polypeptide of the presentinvention which they recognize or specifically bind. The epitope(s) orpolypeptide portion(s) may be specified as described herein, e.g., byN-terminal and C-terminal positions, or by size in contiguous amino acidresidues, or listed in the Tables and Figures. Preferred epitopes of theinvention include the predicted epitopes shown in Table 1B, as well aspolynucleotides that encode these epitopes. Antibodies whichspecifically bind any epitope or polypeptide of the present inventionmay also be excluded. Therefore, the present invention includesantibodies that specifically bind polypeptides of the present invention,and allows for the exclusion of the same.

Antibodies of the present invention may also be described or specifiedin terms of their cross-reactivity. Antibodies that do not bind anyother analog, ortholog, or homolog of a polypeptide of the presentinvention are included. Antibodies that bind polypeptides with at least95%, at least 90%, at least 85%, at least 80%, at least 75%, at least70%, at least 65%, at least 60%, at least 55%, and at least 50% identity(as calculated using methods known in the art and described herein) to apolypeptide of the present invention are also included in the presentinvention. In specific embodiments, antibodies of the present inventioncross-react with murine, rat and/or rabbit homologs of human proteinsand the corresponding epitopes thereof. Antibodies that do not bindpolypeptides with less than 95%, less than 90%, less than 85%, less than80%, less than 75%, less than 70%, less than 65%, less than 60%, lessthan 55%, and less than 50% identity (as calculated using methods knownin the art and described herein) to a polypeptide of the presentinvention are also included in the present invention. In a specificembodiment, the above-described cross-reactivity is with respect to anysingle specific antigenic or immunogenic polypeptide, or combination(s)of 2, 3, 4, 5, or more of the specific antigenic and/or immunogenicpolypeptides disclosed herein. Further included in the present inventionare antibodies which bind polypeptides encoded by polynucleotides whichhybridize to a polynucleotide of the present invention under stringenthybridization conditions (as described herein). Antibodies of thepresent invention may also be described or specified in terms of theirbinding affinity to a polypeptide of the invention. Preferred bindingaffinities include those with a dissociation constant or K_(d) less than5×10⁻² M, 10⁻² M, 5×10 ⁻³M, 10⁻³M, 5×10⁻⁴ M, 10⁻⁴M, 5×10⁻⁵M, 10⁻⁵M,5×10⁻⁶M, 10⁻⁶ M, 5×10⁻⁷ M, 5×10⁻⁸ M, 10⁻⁸ M, 5×10⁻⁹ M, 10⁻⁹ M, 5×10⁻¹⁰M, 10⁻¹⁰ M, 5×10⁻¹¹ M, 10⁻¹¹ M, 5×10⁻¹² M, 10⁻¹² M, 5×10⁻¹³ M, 10⁻¹³ M,5×10⁻¹⁴ M, 10⁻¹⁴ M, 5×10⁻¹⁵ M, or 10⁻¹⁵ M.

The invention also provides antibodies that competitively inhibitbinding of an antibody to an epitope of the invention as determined byany method known in the art for determining competitive binding, forexample, the immunoassays described herein. In preferred embodiments,the antibody competitively inhibits binding to the epitope by at least95%, at least 90%, at least 85%, at least 80%, at least 75%, at least70%, at least 60%, or at least 50%.

Antibodies of the present invention may act as agonists or antagonistsof the polypeptides of the present invention. For example, the presentinvention includes antibodies which disrupt the receptor/ligandinteractions with the polypeptides of the invention either partially orfully. Preferably, antibodies of the present invention bind an antigenicepitope disclosed herein, or a portion thereof. The invention featuresboth receptor-specific antibodies and ligand-specific antibodies. Theinvention also features receptor-specific antibodies which do notprevent ligand binding but prevent receptor activation. Receptoractivation (i.e., signaling) may be determined by techniques describedherein or otherwise known in the art. For example, receptor activationcan be determined by detecting the phosphorylation (e.g., tyrosine orserine/threonine) of the receptor or its substrate byimmunoprecipitation followed by western blot analysis (for example, asdescribed supra). In specific embodiments, antibodies are provided thatinhibit ligand activity or receptor activity by at least 95%, at least90%, at least 85%, at least 80%, at least 75%, at least 70%, at least60%, or at least 50% of the activity in absence of the antibody.

The invention also features receptor-specific antibodies which bothprevent ligand binding and receptor activation as well as antibodiesthat recognize the receptor-ligand complex, and, preferably, do notspecifically recognize the unbound receptor or the unbound ligand.Likewise, included in the invention are neutralizing antibodies whichbind the ligand and prevent binding of the ligand to the receptor, aswell as antibodies which bind the ligand, thereby preventing receptoractivation, but do not prevent the ligand from binding the receptor.Further included in the invention are antibodies which activate thereceptor. These antibodies may act as receptor agonists, i.e.,potentiate or activate either all or a subset of the biologicalactivities of the ligand-mediated receptor activation, for example, byinducing dimerization of the receptor. The antibodies may be specifiedas agonists, antagonists or inverse agonists for biological activitiescomprising the specific biological activities of the peptides of theinvention disclosed herein. The above antibody agonists can be madeusing methods known in the art. See, e.g., PCT publication WO 96/40281;U.S. Pat. No. 5,811,097; Deng et al., Blood 92(6):1981-1988 (1998); Chenet al., Cancer Res. 58(16):3668-3678 (1998); Harrop et al., J. Immunol.161(4):1786-1794 (1998); Zhu et al., Cancer Res. 58(15):3209-3214(1998); Yoon et al., J. Immunol. 160(7):3170-3179 (1998); Prat et al.,J. Cell. Sci. 111(Pt2):237-247 (1998); Pitard et al., J. Immunol.Methods 205(2):177-190 (1997); Liautard et al., Cytokine 9(4):233-241(1997); Carlson et al., J. Biol. Chem. 272(17):11295-11301 (1997);Taryman et al., Neuron 14(4):755-762 (1995); Muller et al., Structure6(9):1153-1167 (1998); Bartunek et al., Cytokine 8(1):14-20 (1996)(which are all incorporated by reference herein in their entireties).

Antibodies of the present invention may be used, for example, to purify,detect, and target the polypeptides of the present invention, includingboth in vitro and in vivo diagnostic and therapeutic methods. Forexample, the antibodies have utility in immunoassays for qualitativelyand quantitatively measuring levels of the polypeptides of the presentinvention in biological samples. See, e.g., Harlow et al., Antibodies: ALaboratory Manual, (Cold Spring Harbor Laboratory Press, 2nd ed. 1988);incorporated by reference herein in its entirety.

As discussed in more detail below, the antibodies of the presentinvention may be used either alone or in combination with othercompositions. The antibodies may further be recombinantly fused to aheterologous polypeptide at the N- or C-terminus or chemicallyconjugated (including covalent and non-covalent conjugations) topolypeptides or other compositions. For example, antibodies of thepresent invention may be recombinantly fused or conjugated to moleculesuseful as labels in detection assays and effector molecules such asheterologous polypeptides, drugs, radionuclides, or toxins. See, e.g.,PCT publications WO 92/08495; WO 91/14438; WO 89/12624; U.S. Pat. No.5,314,995; and EP 396,387; the disclosures of which are incorporatedherein by reference in their entireties.

The antibodies of the invention include derivatives that are modified,i.e, by the covalent attachment of any type of molecule to the antibodysuch that covalent attachment does not prevent the antibody fromgenerating an anti-idiotypic response. For example, but not by way oflimitation, the antibody derivatives include antibodies that have beenmodified, e.g., by glycosylation, acetylation, pegylation,phosphylation, amidation, derivatization by known protecting/blockinggroups, proteolytic cleavage, linkage to a cellular ligand or otherprotein, etc. Any of numerous chemical modifications may be carried outby known techniques, including, but not limited to specific chemicalcleavage, acetylation, formylation, metabolic synthesis of tunicamycin,etc. Additionally, the derivative may contain one or more non-classicalamino acids.

The antibodies of the present invention may be generated by any suitablemethod known in the art. Polyclonal antibodies to an antigen-of-interestcan be produced by various procedures well known in the art. Forexample, a polypeptide of the invention can be administered to varioushost animals including, but not limited to, rabbits, mice, rats, etc. toinduce the production of sera containing polyclonal antibodies specificfor the antigen. Various adjuvants may be used to increase theimmunological response, depending on the host species, and include butare not limited to, Freund's (complete and incomplete), mineral gelssuch as aluminum hydroxide, surface active substances such aslysolecithin, pluronic polyols, polyanions, peptides, oil emulsions,keyhole limpet hemocyanins, dinitrophenol, and potentially useful humanadjuvants such as BCG (bacilue Calmette-Guerin) and corynebacteriumparvum. Such adjuvants are also well known in the art.

Monoclonal antibodies can be prepared using a wide variety of techniquesknown in the art including the use of hybridoma, recombinant, and phagedisplay technologies, or a combination thereof. For example, monoclonalantibodies can be produced using hybridoma techniques including thoseknown in the art and taught, for example, in Harlow et al., Antibodies:A Laboratory Manual, (Cold Spring Harbor Laboratory Press, 2nd ed.1988); Hammerling, et al., in: Monoclonal Antibodies and T-CellHybridomas 563-681 (Elsevier, N.Y., 1981) (said references incorporatedby reference in their entireties). The term “monoclonal antibody” asused herein is not limited to antibodies produced through hybridomatechnology. The term “monoclonal antibody” refers to an antibody that isderived from a single clone, including any eukaryotic, prokaryotic, orphage clone, and not the method by which it is produced.

Methods for producing and screening for specific antibodies usinghybridoma technology are routine and well known in the art and arediscussed in detail in the Examples. In a non-limiting example, mice canbe immunized with a polypeptide of the invention or a cell expressingsuch peptide. Once an immune response is detected, e.g., antibodiesspecific for the antigen are detected in the mouse serum, the mousespleen is harvested and splenocytes isolated. The splenocytes are thenfused by well known techniques to any suitable myeloma cells, forexample cells from cell line SP20 available from the ATCC. Hybridomasare selected and cloned by limited dilution. The hybridoma clones arethen assayed by methods known in the art for cells that secreteantibodies capable of binding a polypeptide of the invention. Ascitesfluid, which generally contains high levels of antibodies, can begenerated by immunizing mice with positive hybridoma clones.

Accordingly, the present invention provides methods of generatingmonoclonal antibodies as well as antibodies produced by the methodcomprising culturing a hybridoma cell secreting an antibody of theinvention wherein, preferably, the hybridoma is generated by fusingsplenocytes isolated from a mouse immunized with an antigen of theinvention with myeloma cells and then screening the hybridomas resultingfrom the fusion for hybridoma clones that secrete an antibody able tobind a polypeptide of the invention.

Another well known method for producing both polyclonal and monoclonalhuman B cell lines is transformation using Epstein Barr Virus (EBV).Protocols for generating EBV-transformed B cell lines are commonly knownin the art, such as, for example, the protocol outlined in Chapter 7.22of Current Protocols in Immunology, Coligan et al., Eds., 1994, JohnWiley & Sons, NY, which is hereby incorporated in its entirety byreference. The source of B cells for transformation is commonly humanperipheral blood, but B cells for transformation may also be derivedfrom other sources including, but not limited to, lymph nodes, tonsil,spleen, tumor tissue, and infected tissues. Tissues are generally madeinto single cell suspensions prior to EBV transformation. Additionally,steps may be taken to either physically remove or inactivate T cells(e.g., by treatment with cyclosporin A) in B cell-containing samples,because T cells from individuals seropositive for anti-EBV antibodiescan suppress B cell immortalization by EBV.

In general, the sample containing human B cells is innoculated with EBV,and cultured for 3-4 weeks. A typical source of EBV is the culturesupernatant of the B95-8 cell line (ATCC #VR-1492). Physical signs ofEBV transformation can generally be seen towards the end of the 3-4 weekculture period. By phase-contrast microscopy, transformed cells mayappear large, clear, hairy and tend to aggregate in tight clusters ofcells. Initially, EBV lines are generally polyclonal. However, overprolonged periods of cell cultures, EBV lines may become monoclonal orpolyclonal as a result of the selective outgrowth of particular B cellclones. Alternatively, polyclonal EBV transformed lines may be subcloned(e.g., by limiting dilution culture) or fused with a suitable fusionpartner and plated at limiting dilution to obtain monoclonal B celllines. Suitable fusion partners for EBV transformed cell lines includemouse myeloma cell lines (e.g., SP2/0, X63-Ag8.653), heteromyeloma celllines (human x mouse; e.g, SPAM-8, SBC-H20, and CB-F7), and human celllines (e.g., GM 1500, SKO-007, RPMI 8226, and KR-4). Thus, the presentinvention also provides a method of generating polyclonal or monoclonalhuman antibodies against polypeptides of the invention or fragmentsthereof, comprising EBV-transformation of human B cells.

Antibody fragments which recognize specific epitopes may be generated byknown techniques. For example, Fab and F(ab′)2 fragments of theinvention may be produced by proteolytic cleavage of immunoglobulinmolecules, using enzymes such as papain (to produce Fab fragments) orpepsin (to produce F(ab′)2 fragments). F(ab′)2 fragments contain thevariable region, the light chain constant region and the CH1 domain ofthe heavy chain.

For example, the antibodies of the present invention can also begenerated using various phage display methods known in the art. In phagedisplay methods, functional antibody domains are displayed on thesurface of phage particles which carry the polynucleotide sequencesencoding them. In a particular embodiment, such phage can be utilized todisplay antigen binding domains expressed from a repertoire orcombinatorial antibody library (e.g., human or murine). Phage expressingan antigen binding domain that binds the antigen of interest can beselected or identified with antigen, e.g., using labeled antigen orantigen bound or captured to a solid surface or bead. Phage used inthese methods are typically filamentous phage including fd and M13binding domains expressed from phage with Fab, Fv or disulfidestabilized Fv antibody domains recombinantly fused to either the phagegene m or gene VIII protein. Examples of phage display methods that canbe used to make the antibodies of the present invention include thosedisclosed in Brinkman et al., J. Immunol. Methods 182:41-50 (1995); Ameset al., J. Immunol. Methods 184:177-186 (1995); Kettleborough et al.,Eur. J. Immunol. 24:952-958 (1994); Persic et al., Gene 187 9-18 (1997);Burton et al., Advances in Immunology 57:191-280 (1994); PCT applicationNo. PCT/GB91/01134; PCT publications WO 90/02809; WO 91/10737; WO92/01047; WO 92/18619; WO 93/11236; WO 95/15982; WO 95/20401; and U.S.Pat. Nos. 5,698,426; 5,223,409; 5,403,484; 5,580,717; 5,427,908;5,750,753; 5,821,047; 5,571,698; 5,427,908; 5,516,637; 5,780,225;5,658,727; 5,733,743 and 5,969,108; each of which is incorporated hereinby reference in its entirety.

As described in the above references, after phage selection, theantibody coding regions from the phage can be isolated and used togenerate whole antibodies, including human antibodies, or any otherdesired antigen binding fragment, and expressed in any desired host,including mammalian cells, insect cells, plant cells, yeast, andbacteria, e.g., as described in detail below. For example, techniques torecombinantly produce Fab, Fab′ and F(ab′)₂ fragments can also beemployed using methods known in the art such as those disclosed in PCTpublication WO 92/22324; Mullinax et al., BioTechniques 12(6):864-869(1992); and Sawai et al., AJRI34:26-34 (1995); and Better et al.,Science 240:1041-1043 (1988) (said references incorporated by referencein their entireties).

Examples of techniques which can be used to produce single-chain Fvs andantibodies include those described in U.S. Pat. Nos. 4,946,778 and5,258,498; Huston et al., Methods in Enzymology 203:46-88 (1991); Shu etal., PNAS 90:7995-7999 (1993); and Skerra et al., Science 240:1038-1040(1988). For some uses, including in vivo use of antibodies in humans andin vitro detection assays, it may be preferable to use chimeric,humanized, or human antibodies. A chimeric antibody is a molecule inwhich different portions of the antibody are derived from differentanimal species, such as antibodies having a variable region derived froma murine monoclonal antibody and a human immunoglobulin constant region.Methods for producing chimeric antibodies are known in the art. Seee.g., Morrison, Science 229:1202 (1985); Oi et al., BioTechniques 4:214(1986); Gillies et al., (1989) J. Immunol. Methods 125:191-202; U.S.Pat. Nos. 5,807,715; 4,816,567; and 4,816397, which are incorporatedherein by reference in their entirety. Humanized antibodies are antibodymolecules from non-human species antibody that binds the desired antigenhaving one or more complementarity determining regions (CDRs) from thenon-human species and a framework regions from a human immunoglobulinmolecule. Often, framework residues in the human framework regions willbe substituted with the corresponding residue from the CDR donorantibody to alter, preferably improve, antigen binding. These frameworksubstitutions are identified by methods well known in the art, e.g., bymodeling of the interactions of the CDR and framework residues toidentify framework residues important for antigen binding and sequencecomparison to identify unusual framework residues at particularpositions. (See, e.g., Queen et al., U.S. Pat. No. 5,585,089; Riechmannet al., Nature 332:323 (1988), which are incorporated herein byreference in their entireties.) Antibodies can be humanized using avariety of techniques known in the art including, for example,CDR-grafting 5,585,089), veneering or resurfacing (EP 592,106; EP519,596; Padlan, Molecular Immunology 28(4/5):489498 (1991); Studnickaet al., Protein Engineering 7(6):805-814 (1994); Roguska. et al., PNAS91:969-973 (1994)), and chain shuffling (U.S. Pat. No. 5,565,332).

Completely human antibodies are particularly desirable for therapeutictreatment of human patients. Human antibodies can be made by a varietyof methods known in the art including phage display methods describedabove using antibody libraries derived from human immunoglobulinsequences. See also, U.S. Pat. Nos. 4,444,887 and 4,716,111; and PCrpublications WO 98/46645, WO 98/50433, WO 98/24893, WO 98/16654, WO96/34096, WO 96/33735, and WO 91/10741; each of which is incorporatedherein by reference in its entirety.

Human antibodies can also be produced using transgenic mice which areincapable of expressing functional endogenous immunoglobulins, but whichcan express human immunoglobulin genes. For example, the human heavy andlight chain immunoglobulin gene complexes may be introduced randomly orby homologous recombination into mouse embryonic stem cells.Alternatively, the human variable region, constant region, and diversityregion may be introduced into mouse embryonic stem cells in addition tothe human heavy and light chain genes. The mouse heavy and light chainimmunoglobulin genes may be rendered non-functional separately orsimultaneously with the introduction of human immunoglobulin loci byhomologous recombination. In particular, homozygous deletion of the JHregion prevents endogenous antibody production. The modified embryonicstem cells are expanded and microinjected into blastocysts to producechimeric mice. The chimeric mice are then bred to produce homozygousoffspring which express human antibodies. The transgenic mice areimmunized in the normal fashion with a selected antigen, e.g., all or aportion of a polypeptide of the invention. Monoclonal antibodiesdirected against the antigen can be obtained from the immunized,transgenic mice using conventional hybridoma technology. The humanimmunoglobulin transgenes harbored by the transgenic mice rearrangeduring B cell differentiation, and subsequently undergo class switchingand somatic mutation. Thus, using such a technique, it is possible toproduce therapeutically useful IgG, IgA, IgM and IgE antibodies. For anoverview of this technology for producing human antibodies, see Lonbergand Huszar, Int. Rev. Immunol. 13:65-93 (1995). For a detaileddiscussion of this technology for producing human antibodies and humanmonoclonal antibodies and protocols for producing such antibodies, see,e.g., PCT publications WO 98/24893; WO 92/01047; WO 96/34096; WO96/33735; European Patent No. 0 598 877; U.S. Pat. Nos. 5,413,923;5,625,126; 5,633,425; 5,569,825; 5,661,016; 5,545,806; 5,814,318;5,885,793; 5,916,771; 5,939,598; 6,075,181; and 6,114,598, which areincorporated by reference herein in their entirety. In addition,companies such as Abgenix, Inc. (Freemont, Calif.) and Genpharm (SanJose, Calif.) can be engaged to provide human antibodies directedagainst a selected antigen using technology similar to that describedabove.

Completely human antibodies which recognize a selected epitope can begenerated using a technique referred to as “guided selection.” In thisapproach a selected non-human monoclonal antibody, e.g., a mouseantibody, is used to guide the selection of a completely human antibodyrecognizing the same epitope. (Jespers et al., Bio/technology 12:899-903(1988)).

Further, antibodies to the polypeptides of the invention can, in turn,be utilized to generate anti-idiotype antibodies that “mimic”polypeptides of the invention using techniques well known to thoseskilled in the art. (See, e.g., Greenspan & Bona, FASEB J. 7(5):437444;(1989) and Nissinoff, J. Immunol. 147(8):2429-2438 (1991)). For example,antibodies which bind to and competitively inhibit polypeptidemultimerization and/or binding of a polypeptide of the invention to aligand can be used to generate anti-idiotypes that “mimic” thepolypeptide multimerization and/or binding domain and, as a consequence,bind to and neutralize polypeptide and/or its ligand. Such neutralizinganti-idiotypes or Fab fragments of such anti-idiotypes can be used intherapeutic regimens to neutralize polypeptide ligand(s)/receptor(s).For example, such anti-idiotypic antibodies can be used to bind apolypeptide of the invention and/or to bind its ligand(s)/receptor(s),and thereby block its biological activity. Alternatively, antibodieswhich bind to and enhance polypeptide multimerization and/or binding,and/or receptor/ligand multimerization, binding and/or signaling can beused to generate anti-idiotypes that function as agonists of apolypeptide of the invention and/or its ligand/receptor. Such agonisticanti-idiotypes or Fab fragments of such anti-idiotypes can be used intherapeutic regimens as agonists of the polypeptides of the invention orits ligand(s)/receptor(s). For example, such anti-idiotypic antibodiescan be used to bind a polypeptide of the invention and/or to bind itsligand(s)/receptor(s), and thereby promote or enhance its biologicalactivity.

Intrabodies of the invention can be produced using methods known in theart, such as those disclosed and reviewed in Chen et al., Hum Gene Ther.5:595-601 (1994); Marasco, W. A., Gene Ther. 4:11-15 (1997); Rondon andMarasco, Annu. Rev. Microbiol. 51:257-283 (1997); Proba et al., J. Mol.Biol. 275:245-253 (1998); Cohen et al., Oncogene 17:2445-2456 (1998);Ohage and Steipe, J. Mol. Biol. 291:1119-1128 (1999); Ohage et al., J.Mol. Biol. 291:1129-1134 (1999); Wirtz and Steipe, Protein Sci.8:2245-2250 (1999); Zhu et al., J. Immunol. Methods 231:207-222 (1999);and references cited therein.

Polynucleotides Encoding Antibodies

The invention further provides polynucleotides comprising a nucleotidesequence encoding an antibody of the invention and fragments thereof.The invention also encompasses polynucleotides that hybridize understringent or alternatively, under lower stringency hybridizationconditions, e.g., as defined supra, to polynucleotides that encode anantibody, preferably, that specifically binds to a polypeptide of theinvention, preferably, an antibody that binds to a polypeptide havingthe amino acid sequence of SEQ ID NO:Y, to a polypeptide encoded by aportion of SEQ ID NO:X as defined in columns 8 and 9 of Table 2, and/orto a polypeptide encoded by the cDNA contained in ATCC Deposit No:Z.

The polynucleotides may be obtained, and the nucleotide sequence of thepolynucleotides determined, by any method known in the art. For example,if the nucleotide sequence of the antibody is known, a polynucleotideencoding the antibody may be assembled from chemically synthesizedoligonucleotides (e.g., as described in Kutmeier et al., BioTechniques17:242 (1994)), which, briefly, involves the synthesis of overlappingoligonucleotides containing portions of the sequence encoding theantibody, annealing and ligating of those oligonucleotides, and thenamplification of the ligated oligonucleotides by PCR.

Alternatively, a polynucleotide encoding an antibody may be generatedfrom nucleic acid from a suitable source. If a clone containing anucleic acid encoding a particular antibody is not available, but thesequence of the antibody molecule is known, a nucleic acid encoding theimmunoglobulin may be chemically synthesized or obtained from a suitablesource (e.g., an antibody cDNA library, or a cDNA library generatedfrom, or nucleic acid, preferably poly A+ RNA, isolated from, any tissueor cells expressing the antibody, such as hybridoma cells selected toexpress an antibody of the invention) by PCR amplification usingsynthetic primers hybridizable to the 3′ and 5′ ends of the sequence orby cloning using an oligonucleotide probe specific for the particulargene sequence to identify, e.g., a cDNA clone from a cDNA library thatencodes the antibody. Amplified nucleic acids generated by PCR may thenbe cloned into replicable cloning vectors using any method well known inthe art.

Once the nucleotide sequence and corresponding amino acid sequence ofthe antibody is determined, the nucleotide sequence of the antibody maybe manipulated using methods well known in the art for the manipulationof nucleotide sequences, e.g., recombinant DNA techniques, site directedmutagenesis, PCR, etc. (see, for example, the techniques described inSambrook et al., 1990, Molecular Cloning, A Laboratory Manual, 2d Ed.,Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y. and Ausubel etal., eds., 1998, Current Protocols in Molecular Biology, John Wiley &Sons, NY, which are both incorporated by reference herein in theirentireties), to generate antibodies having a different amino acidsequence, for example to create amino acid substitutions, deletions,and/or insertions.

In a specific embodiment, the amino acid sequence of the heavy and/orlight chain variable domains may be inspected to identify the sequencesof the complementarity determining regions (CDRs) by methods that arewell know in the art, e.g., by comparison to known amino acid sequencesof other heavy and light chain variable regions to determine the regionsof sequence hypervariability. Using routine recombinant DNA techniques,one or more of the CDRs may be inserted within framework regions, e.g.,into human framework regions to humanize a non-human antibody, asdescribed supra. The framework regions may be naturally occurring orconsensus framework regions, and preferably human framework regions(see, e.g., Chothia et al., J. Mol. Biol. 278: 457-479 (1998) for alisting of human framework regions). Preferably, the polynucleotidegenerated by the combination of the framework regions and CDRs encodesan antibody that specifically binds a polypeptide of the invention.Preferably, as discussed supra, one or more amino acid substitutions maybe made within the framework regions, and, preferably, the amino acidsubstitutions improve binding of the antibody to its antigen.Additionally, such methods may be used to make amino acid substitutionsor deletions of one or more variable region cysteine residuesparticipating in an intrachain disulfide bond to generate antibodymolecules lacking one or more intrachain disulfide bonds. Otheralterations to the polynucleotide are encompassed by the presentinvention and within the skill of the art.

In addition, techniques developed for the production of “chimericantibodies” (Morrison et al., Proc. Natl. Acad. Sci. 81:851-855 (1984);Neuberger et al., Nature 312:604-608 (1984); Takeda et al., Nature314:452454 (1985)) by splicing genes from a mouse antibody molecule ofappropriate antigen specificity together with genes from a humanantibody molecule of appropriate biological activity can be used. Asdescribed supra, a chimeric antibody is a molecule in which differentportions are derived from different animal species, such as those havinga variable region derived from a murine mAb and a human immunoglobulinconstant region, e.g., humanized antibodies.

Alternatively, techniques described for the production of single chainantibodies (U.S. Pat. No. 4,946,778; Bird, Science 242:423-42 (1988);Huston et al., Proc. Natl. Acad. Sci. USA 85:5879-5883 (1988); and Wardet al., Nature 334:544-54 (1989)) can be adapted to produce single chainantibodies. Single chain antibodies are formed by linking the heavy andlight chain fragments of the Fv region via an amino acid bridge,resulting in a single chain polypeptide. Techniques for the assembly offunctional Fv fragments in E. coli may also be used (Skerra et al.,Science 242:1038-1041 (1988)).

Methods of Producing Antibodies

The antibodies of the invention can be produced by any method known inthe art for the synthesis of antibodies, in particular, by chemicalsynthesis or preferably, by recombinant expression techniques. Methodsof producing antibodies include, but are not limited to, hybridomatechnology, EBV transformation, and other methods discussed herein aswell as through the use recombinant DNA technology, as discussed below.

Recombinant expression of an antibody of the invention, or fragment,derivative or analog thereof, (e.g., a heavy or light chain of anantibody of the invention or a single chain antibody of the invention),requires construction of an expression vector containing apolynucleotide that encodes the antibody. Once a polynucleotide encodingan antibody molecule or a heavy or light chain of an antibody, orportion thereof (preferably containing the heavy or light chain variabledomain), of the invention has been obtained, the vector for theproduction of the antibody molecule may be produced by recombinant DNAtechnology using techniques well known in the art. Thus, methods forpreparing a protein by expressing a polynucleotide containing anantibody encoding nucleotide sequence are described herein. Methodswhich are well known to those skilled in the art can be used toconstruct expression vectors containing antibody coding sequences andappropriate transcriptional and translational control signals. Thesemethods include, for example, in vitro recombinant DNA techniques,synthetic techniques, and in vivo genetic recombination. The invention,thus, provides replicable vectors comprising a nucleotide sequenceencoding an antibody molecule of the invention, or a heavy or lightchain thereof, or a heavy or light chain variable domain, operablylinked to a promoter. Such vectors may include the nucleotide sequenceencoding the constant region of the antibody molecule (see, e.g., PCTPublication WO 86/05807; PCT Publication WO 89/01036; and U.S. Pat. No.5,122,464) and the variable domain of the antibody may be cloned intosuch a vector for expression of the entire heavy or light chain.

The expression vector is transferred to a host cell by conventionaltechniques and the transfected cells are then cultured by conventionaltechniques to produce an antibody of the invention. Thus, the inventionincludes host cells containing a polynucleotide encoding an antibody ofthe invention, or a heavy or light chain thereof, or a single chainantibody of the invention, operably linked to a heterologous promoter.In preferred embodiments for the expression of double-chainedantibodies, vectors encoding both the heavy and light chains may beco-expressed in the host cell for expression of the entireimmunoglobulin molecule, as detailed below.

A variety of host-expression vector systems may be utilized to expressthe antibody molecules of the invention. Such host-expression systemsrepresent vehicles by which the coding sequences of interest may beproduced and subsequently purified, but also represent cells which may,when transformed or transfected with the appropriate nucleotide codingsequences, express an antibody molecule of the invention in situ. Theseinclude but are not limited to microorganisms such as bacteria (e.g., E.coli, B. subtilis) transformed with recombinant bacteriophage DNA,plasmid DNA or cosmid DNA expression vectors containing antibody codingsequences; yeast (e.g., Saccharomyces, Pichia) transformed withrecombinant yeast expression vectors containing antibody codingsequences; insect cell systems infected with recombinant virusexpression vectors (e.g., baculovirus) containing antibody codingsequences; plant cell systems infected with recombinant virus expressionvectors (e.g., cauliflower mosaic virus, CaMV; tobacco mosaic virus,TMV) or transformed with recombinant plasmid expression vectors (e.g.,Ti plasmid) containing antibody coding sequences; or mammalian cellsystems (e.g., COS, CHO, BHK, 293, 3T3 cells) harboring recombinantexpression constructs containing promoters derived from the genome ofmammalian cells (e.g., metallothionein promoter) or from mammalianviruses (e.g., the adenovirus late promoter; the vaccinia virus 7.5Kpromoter). Preferably, bacterial cells such as Escherichia coli, andmore preferably, eukaryotic cells, especially for the expression ofwhole recombinant antibody molecule, are used for the expression of arecombinant antibody molecule. For example, mammalian cells such asChinese hamster ovary cells (CHO), in conjunction with a vector such asthe major intermediate early gene promoter element from humancytomegalovirus is an effective expression system for antibodies(Foecking et al., Gene 45:101 (1986); Cockett et al., Bio/Technology 8:2(1990)).

In bacterial systems, a number of expression vectors may beadvantageously selected depending upon the use intended for the antibodymolecule being expressed. For example, when a large quantity of such aprotein is to be produced, for the generation of pharmaceuticalcompositions of an antibody molecule, vectors which direct theexpression of high levels of fusion protein products that are readilypurified may be desirable. Such vectors include, but are not limited, tothe E. coli expression vector pUR278 (Ruther et al., EMBO J. 2:1791(1983)), in which the antibody coding sequence may be ligatedindividually into the vector in frame with the lac Z coding region sothat a fusion protein is produced; pIN vectors (Inouye & Inouye, NucleicAcids Res. 13:3101-3109 (1985); Van Heeke & Schuster, J. Biol. Chem.24:5503-5509 (1989)); and the like. pGEX vectors may also be used toexpress foreign polypeptides as fusion proteins with glutathioneS-transferase (GST). In general, such fusion proteins are soluble andcan easily be purified from lysed cells by adsorption and binding tomatrix glutathione-agarose beads followed by elution in the presence offree glutathione. The pGEX vectors are designed to include thrombin orfactor Xa protease cleavage sites so that the cloned target gene productcan be released from the GST moiety.

In an insect system, Autographa californica nuclear polyhedrosis virus(AcNPV) is used as a vector to express foreign genes. The virus grows inSpodoptera frugiperda cells. The antibody coding sequence may be clonedindividually into non-essential regions (for example the polyhedringene) of the virus and placed under control of an AcNPV promoter (forexample the polyhedrin promoter).

In mammalian host cells, a number of viral-based expression systems maybe utilized. In cases where an adenovirus is used as an expressionvector, the antibody coding sequence of interest may be ligated to anadenovirus transcription/translation control complex, e.g., the latepromoter and tripartite leader sequence. This chimeric gene may then beinserted in the adenovirus genome by in vitro or in vivo recombination.Insertion in a non-essential region of the viral genome (e.g., region E1or E3) will result in a recombinant virus that is viable and capable ofexpressing the antibody molecule in infected hosts. (e.g., see Logan &Shenk, Proc. Natl. Acad. Sci. USA 81:355-359 (1984)). Specificinitiation signals may also be required for efficient translation ofinserted antibody coding sequences. These signals include the ATGinitiation codon and adjacent sequences. Furthermore, the initiationcodon must be in phase with the reading frame of the desired codingsequence to ensure translation of the entire insert. These exogenoustranslational control signals and initiation codons can be of a varietyof origins, both natural and synthetic. The efficiency of expression maybe enhanced by the inclusion of appropriate transcription enhancerelements, transcription terminators, etc. (see Bittner et al., Methodsin Enzymol. 153:51-544 (1987)).

In addition, a host cell strain may be chosen which modulates theexpression of the inserted sequences, or modifies and processes the geneproduct in the specific fashion desired. Such modifications (e.g.,glycosylation) and processing (e.g., cleavage) of protein products maybe important for the function of the protein. Different host cells havecharacteristic and specific mechanisms for the post-translationalprocessing and modification of proteins and gene products. Appropriatecell lines or host systems can be chosen to ensure the correctmodification and processing of the foreign protein expressed. To thisend, eukaryotic host cells which possess the cellular machinery forproper processing of the primary transcript, glycosylation, andphosphorylation of the gene product may be used. Such mammalian hostcells include but are not limited to CHO, VERY, BHK, Hela, COS, MDCK,293, 3T3, WI38, and in particular, breast cancer cell lines such as, forexample, BT483, Hs578T, HTB2, BT20 and T47D, and normal mammary glandcell line such as, for example, CRL7030 and Hs578Bst.

For long-term, high-yield production of recombinant proteins, stableexpression is preferred. For example, cell lines which stably expressthe antibody molecule may be engineered. Rather than using expressionvectors which contain viral origins of replication, host cells can betransformed with DNA controlled by appropriate expression controlelements (e.g., promoter, enhancer, sequences, transcriptionterminators, polyadenylation sites, etc.), and a selectable marker.Following the introduction of the foreign DNA, engineered cells may beallowed to grow for 1-2 days in an enriched media, and then are switchedto a selective media. The selectable marker in the recombinant plasmidconfers resistance to the selection and allows cells to stably integratethe plasmid into their chromosomes and grow to form foci which in turncan be cloned and expanded into cell lines. This method mayadvantageously be used to engineer cell lines which express the antibodymolecule. Such engineered cell lines may be particularly useful inscreening and evaluation of compounds that interact directly orindirectly with the antibody molecule.

A number of selection systems may be used, including but not limited tothe herpes simplex virus thymidine kinase (Wigler et al., Cell 11:223(1977)), hypoxanthine-guanine phosphoribosyltransferase (Szybalska &Szybalski, Proc. Natl. Acad. Sci. USA 48:202 (1992)), and adeninephosphoribosyltransferase (Lowy et al., Cell 22:817 (1980)) genes can beemployed in tk-, hgprt- or aprt- cells, respectively. Also,antimetabolite resistance can be used as the basis of selection for thefollowing genes: dhfr, which confers resistance to methotrexate (Wigleret al., Natl. Acad. Sci. USA 77:357 (1980); O'Hare et al., Proc. Natl.Acad. Sci. USA 78:1527 (1981)); gpt, which confers resistance tomycophenolic acid (Mulligan & Berg, Proc. Natl. Acad. Sci. USA 78:2072(1981)); neo, which confers resistance to the aminoglycoside G-418Clinical Pharmacy 12:488-505; Wu and Wu, Biotherapy 3:87-95 (1991);Tolstoshev, Ann. Rev. Pharmacol. Toxicol. 32:573-596 (1993); Mulligan,Science 260:926-932 (1993); and Morgan and Anderson, Ann. Rev. Biochem.62:191-217 (1993); May, 1993, TIB TECH 11(5):155-215 (1993)); and hygro,which confers resistance to hygromycin (Santerre et al., Gene 30:147(1984)). Methods commonly known in the art of recombinant DNA technologymay be routinely applied to select the desired recombinant clone, andsuch methods are described, for example, in Ausubel et al. (eds.),Current Protocols in Molecular Biology, John Wiley & Sons, NY (1993);Kriegler, Gene Transfer and Expression, A Laboratory Manual, StocktonPress, NY (1990); and in Chapters 12 and 13, Dracopoli et al. (eds),Current Protocols in Human Genetics, John Wiley & Sons, NY (1994);Colberre-Garapin et al., J. Mol. Biol. 150:1 (1981), which areincorporated by reference herein in their entireties.

The expression levels of an antibody molecule can be increased by vectoramplification (for a review, see Bebbington and Hentschel, The use ofvectors based on gene amplification for the expression of cloned genesin mammalian cells in DNA cloning, Vol.3. (Academic Press, New York,1987)). When a marker in the vector system expressing antibody isamplifiable, increase in the level of inhibitor present in culture ofhost cell will increase the number of copies of the marker gene. Sincethe amplified region is associated with the antibody gene, production ofthe antibody will also increase (Crouse et al., Mol. Cell. Biol. 3:257(1983)).

Vectors which use glutamine synthase (GS) or DHFR as the selectablemarkers can be amplified in the presence of the drugs methioninesulphoximine or methotrexate, respectively. An advantage of glutaminesynthase based vectors are the availabilty of cell lines (e.g., themurine myeloma cell line, NSO) which are glutamine synthase negative.Glutamine synthase expression systems can also function in glutaminesynthase expressing cells (e.g. Chinese Hamster Ovary (CHO) cells) byproviding additional inhibitor to prevent the functioning of theendogenous gene. A glutamine synthase expression system and componentsthereof are detailed in PCT publications: WO87/04462; WO86/05807;WO89/01036; WO89/10404; and WO91/06657 which are incorporated in theirentireties by reference herein. Additionally, glutamine synthaseexpression vectors that may be used according to the present inventionare commercially available from suppliers, including, for example LonzaBiologics, Inc. (Portsmouth, N.Mex. Expression and production ofmonoclonal antibodies using a GS expression system in murine myelomacells is described in Bebbington et al., Bio/technology 10:169(1992) andin Biblia and Robinson Biotechnol. Prog. 11:1 (1995) which areincorporated in their entirities by reference herein.

The host cell may be co-transfected with two expression vectors of theinvention, the first vector encoding a heavy chain derived polypeptideand the second vector encoding a light chain derived polypeptide. Thetwo vectors may contain identical selectable markers which enable equalexpression of heavy and light chain polypeptides. Alternatively, asingle vector may be used which encodes, and is capable of expressing,both heavy and light chain polypeptides. In such situations, the lightchain should be placed before the heavy chain to avoid an excess oftoxic free heavy chain (Proudfoot, Nature 322:52 (1986); Kohler, Proc.Natl. Acad. Sci. USA 77:2197 (1980)). The coding sequences for the heavyand light chains may comprise cDNA or genomic DNA.

Once an antibody molecule of the invention has been produced by ananimal, chemically synthesized, or recombinantly expressed, it may bepurified by any method known in the art for purification of animmunoglobulin molecule, for example, by chromatography (e.g., ionexchange, affinity, particularly by affinity for the specific antigenafter Protein A, and sizing column chromatography), centrifugation,differential solubility, or by any other standard technique for thepurification of proteins. In addition, the antibodies of the presentinvention or fragments thereof can be fused to heterologous polypeptidesequences described herein or otherwise known in the art, to facilitatepurification.

The present invention encompasses antibodies recombinantly fused orchemically conjugated (including both covalently and non-covalentlyconjugations) to a polypeptide (or portion thereof, preferably at least10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 amino acids of thepolypeptide) of the present invention to generate fusion proteins. Thefusion does not necessarily need to be direct, but may occur throughlinker sequences. The antibodies may be specific for antigens other thanpolypeptides (or portion thereof, preferably at least 10, 20, 30, 40,50, 60, 70, 80, 90 or 100 amino acids of the polypeptide) of the presentinvention. For example, antibodies may be used to target thepolypeptides of the present invention to particular cell types, eitherin vitro or in vivo, by fusing or conjugating the polypeptides of thepresent invention to antibodies specific for particular cell surfacereceptors. Antibodies fused or conjugated to the polypeptides of thepresent invention may also be used in in vitro immunoassays andpurification methods using methods known in the art. See e.g., Harbor etal., supra, and PCT publication WO 93/21232; EP 439,095; Naramura etal., Immunol. Lett. 39:91-99 (1994); U.S. Pat. No. 5,474,981; Gillies etal., PNAS 89:1428-1432 (1992); Fell et al., J. Immunol. 146:2446-2452(1991), which are incorporated by reference in their entireties.

The present invention further includes compositions comprising thepolypeptides of the present invention fused or conjugated to antibodydomains other than the variable regions. For example, the polypeptidesof the present invention may be fused or conjugated to an antibody Fcregion, or portion thereof. The antibody portion fused to a polypeptideof the present invention may comprise the constant region, hinge region,CH1 domain, CH2 domain, and CH3 domain or any combination of wholedomains or portions thereof. The polypeptides may also be fused orconjugated to the above antibody portions to form multimers. Forexample, Fc portions fused to the polypeptides of the present inventioncan form dimers through disulfide bonding between the Fc portions.Higher multimeric forms can be made by fusing the polypeptides toportions of IgA and IgM. Methods for fusing or conjugating thepolypeptides of the present invention to antibody portions are known inthe art. See, e.g., U.S. Pat. Nos. 5,336,603; 5,622,929; 5,359,046;5,349,053; 5,447,851; 5,112,946; EP 307,434; EP 367,166; PCTpublications WO 96/04388; WO 91/06570; Ashkenazi et al., Proc. Natl.Acad. Sci. USA 88:10535-10539 (1991); Zheng et al., J. Immunol.154:5590-5600 (1995); and Vil et al., Proc. Natl. Acad. Sci. USA89:11337-11341 (1992) (said references incorporated by reference intheir entireties).

As discussed, supra, the polypeptides corresponding to a polypeptide,polypeptide fragment, or a variant of SEQ ID NO:Y may be fused orconjugated to the above antibody portions to increase the in vivo halflife of the polypeptides or for use in immunoassays using methods knownin the art. Further, the polypeptides corresponding to SEQ ID NO:Y maybe fused or conjugated to the above antibody portions to facilitatepurification. One reported example describes chimeric proteinsconsisting of the first two domains of the human CD4-polypeptide andvarious domains of the constant regions of the heavy or light chains ofmammalian immunoglobulins. See EP 394,827; and Traunecker et al., Nature331:84-86 (1988). The polypeptides of the present invention fused orconjugated to an antibody having disulfide-linked dimeric structures(due to the IgG) may also be more efficient in binding and neutralizingother molecules, than the monomeric secreted protein or protein fragmentalone. See, for example, Fountoulakis et al., J. Biochem. 270:3958-3964(1995). In many cases, the Fc part in a fusion protein is beneficial intherapy and diagnosis, and thus can result in, for example, improvedpharmacokinetic properties. See, for example, EP A 232,262.Alternatively, deleting the fc part after the fusion protein has beenexpressed, detected, and purified, would be desired. For example, the Fcportion may hinder therapy and diagnosis if the fusion protein is usedas an antigen for immunizations. In drug discovery, for example, humanproteins, such as hIL-5, have been fused with Fc portions for thepurpose of high-throughput screening assays to identify antagonists ofhiL-5. (See, Bennett et al., J. Molecular Recognition 8:52-58 (1995);Johanson et al., J. Biol. Chem. 270:9459-9471 (1995)).

Moreover, the antibodies or fragments thereof of the present inventioncan be fused to marker sequences, such as a peptide to facilitatepurification. In preferred embodiments, the marker amino acid sequenceis a hexa-histidine peptide, such as the tag provided in a pQE vector(QIAGEN, Inc., 9259 Eton Avenue, Chatsworth, Calif., 91311), amongothers, many of which are commercially available. As described in Gentzet al., Proc. Natl. Acad. Sci. USA 86:821-824 (1989), for instance,hexa-histidine provides for convenient purification of the fusionprotein. Other peptide tags useful for purification include, but are notlimited to, the “MA” tag, which corresponds to an epitope derived fromthe influenza hemagglutinin protein (Wilson et al., Cell 37:767 (1984))and the “flag” tag.

The present invention further encompasses antibodies or fragmentsthereof conjugated to a diagnostic or therapeutic agent. The antibodiescan be used diagnostically to, for example, monitor the development orprogression of a tumor as part of a clinical testing procedure to, e.g.,determine the efficacy of a given treatment regimen. Detection can befacilitated by coupling the antibody to a detectable substance. Examplesof detectable substances include various enzymes, prosthetic groups,fluorescent materials, luminescent materials, bioluminescent materials,radioactive materials, positron emitting metals using various positronemission tomographies, and nonradioactive paramagnetic metal ions. Thedetectable substance may be coupled or conjugated either directly to theantibody (or fragment thereof) or indirectly, through an intermediate(such as, for example, a linker known in the art) using techniques knownin the art. See, for example, U.S. Pat. No. 4,741,900 for metal ionswhich can be conjugated to antibodies for use as diagnostics accordingto the present invention. Examples of suitable enzymes includehorseradish peroxidase, alkaline phosphatase, beta-galactosidase, oracetylcholinesterase; examples of suitable prosthetic group complexesinclude streptavidin/biotin and avidin/biotin; examples of suitablefluorescent materials include umbelliferone, fluorescein, fluoresceinisothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansylchloride or phycoerythrin; an example of a luminescent material includesluminol; examples of bioluminescent materials include luciferase,luciferin, and aequorin; and examples of suitable radioactive materialinclude 125I, 131I, 111In or 99Tc.

Further, an antibody or fragment thereof may be conjugated to atherapeutic moiety such as a cytotoxin, e.g., a cytostatic or cytocidalagent, a therapeutic agent or a radioactive metal ion, e.g.,alpha-emitters such as, for example, 213Bi. A cytotoxin or cytotoxicagent includes any agent that is detrimental to cells. Examples includepaclitaxol, cytochalasin B, gramicidin D, ethidium bromide, emetine,mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicin,doxorubicin, daunorubicin, dihydroxy anthracin dione, mitoxantrone,mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids,procaine, tetracaine, lidocaine, propranolol, and puromycin and analogsor homologs thereof. Therapeutic agents include, but are not limited to,antimetabolites (e.g., methotrexate, 6-mercaptopurine, 6-thioguanine,cytarabine, 5-fluorouracil decarbazine), alkylating agents (e.g.,mechlorethamine, thioepa chlorambucil, melphalan, carmustine (BSNU) andlomustine (CCNU), cyclothosphamide, busulfan, dibromomannitol,streptozotocin, mitomycin C, and cis-dichlorodiamine platinum (II)(DDP)cisplatin), anthracyclines (e.g., daunorubicin (formerlydaunomycin) and doxorubicin), antibiotics (e.g., dactinomycin (formerlyactinomycin), bleomycin, mithramycin, and anthramycin (AMC)), andanti-mitotic agents (e.g., vincristine and vinblastine).

The conjugates of the invention can be used for modifying a givenbiological response, the therapeutic agent or drug moiety is not to beconstrued as limited to classical chemical therapeutic agents. Forexample, the drug moiety may be a protein or polypeptide possessing adesired biological activity. Such proteins may include, for example, atoxin such as abrin, ricin A, pseudomonas exotoxin, or diphtheria toxin;a protein such as tumor necrosis factor, α-interferon, β-interferon,nerve growth factor, platelet derived growth factor, tissue plasminogenactivator, an apoptotic agent, e.g., TNF-alpha, TNF-beta, AIM I (See,International Publication No. WO 97/33899), AIM II (See, InternationalPublication No. WO 97/34911), Fas Ligand (Takahashi et al., Int.Immunol., 6:1567-1574 (1994)), VEGI (See, International Publication No.WO 99/23105), a thrombotic agent or an anti-angiogenic agent, e.g.,angiostatin or endostatin; or, biological response modifiers such as,for example, lymphokines, interleukin-1 (“IL-1”), interleukin-2(“IL-2”), interleukin-6 (“IL-6”), granulocyte macrophage colonystimulating factor (“GM-CSF”), granulocyte colony stimulating factor(“G-CSF”), or other growth factors.

Antibodies may also be attached to solid supports, which areparticularly useful for immunoassays or purification of the targetantigen. Such solid supports include, but are not limited to, glass,cellulose, polyacrylaride, nylon, polystyrene, polyvinyl chloride orpolypropylene.

Techniques for conjugating such therapeutic moiety to antibodies arewell known. See, for example, Arnon et al., “Monoclonal Antibodies ForImmunotargeting Of Drugs In Cancer Therapy”, in Monoclonal AntibodiesAnd Cancer Therapy, Reisfeld et al. (eds.), pp. 243-56 (Alan R. Liss,Inc. 1985); Hellstrom et al., “Antibodies For Drug Delivery”, inControlled Drug Delivery (2nd Ed.), Robinson et al. (eds.), pp. 623-53(Marcel Dekker, Inc. 1987); Thorpe, “Antibody Carriers Of CytotoxicAgents In Cancer Therapy: A Review”, in Monoclonal Antibodies '84:Biological And Clinical Applications, Pinchera et al. (eds.), pp.475-506 (1985); “Analysis, Results, And Future Prospective Of TheTherapeutic Use Of Radiolabeled Antibody In Cancer Therapy”, inMonoclonal Antibodies For Cancer Detection And Therapy, Baldwin et al.(eds.), pp. 303-16 (Academic Press 1985), and Thorpe et al., “ThePreparation And Cytotoxic Properties Of Antibody-Toxin Conjugates”,Immunol. Rev. 62:119-58 (1982).

Alternatively, an antibody can be conjugated to a second antibody toform an antibody heteroconjugate as described by Segal in U.S. Pat. No.4,676,980, which is incorporated herein by reference in its entirety.

An antibody, with or without a therapeutic moiety conjugated to it,administered alone or in combination with cytotoxic factor(s) and/orcytokine(s) can be used as a therapeutic.

Immunophenotyping

The antibodies of the invention may be utilized for immunophenotyping ofcell lines and biological samples. Translation products of the gene ofthe present invention may be useful as cell-specific markers, or morespecifically as cellular markers that are differentially expressed atvarious stages of differentiation and/or maturation of particular celltypes. Monoclonal antibodies directed against a specific epitope, orcombination of epitopes, will allow for the screening of cellularpopulations expressing the marker. Various techniques can be utilizedusing monoclonal antibodies to screen for cellular populationsexpressing the marker(s), and include magnetic separation usingantibody-coated magnetic beads, “panning” with antibody attached to asolid matrix (i.e., plate), and flow cytometry (See, e.g., U.S. Pat. No.5,985,660; and Morrison et al., Cell, 96:737-49 (1999)).

These techniques allow for the screening of particular populations ofcells, such as might be found with hematological malignancies (i.e.minimal residual disease (MRD) in acute leukemic patients) and“non-self” cells in transplantations to prevent Graft-versus-HostDisease (GVHD). Alternatively, these techniques allow for the screeningof hematopoietic stem and progenitor cells capable of undergoingproliferation and/or differentiation, as might be found in humanumbilical cord blood.

Assays For Antibody Binding

The antibodies of the invention may be assayed for immunospecificbinding by any method known in the art. The immunoassays which can beused include but are not limited to competitive and non-competitiveassay systems using techniques such as western blots, radioimmunoassays,ELISA (enzyme linked immunosorbent assay), “sandwich” immunoassays,immunoprecipitation assays, precipitin reactions, gel diffusionprecipitin reactions, immunodiffusion assays, agglutination assays,complement-fixation assays, immunoradiometric assays, fluorescentimmunoassays, and protein A immunoassays, to name but a few. Such assaysare routine and well known in the art (see, e.g., Ausubel et al, eds,1994, Current Protocols in Molecular Biology, Vol. 1, John Wiley & Sons,Inc., New York, which is incorporated by reference herein in itsentirety). Exemplary immunoassays are described briefly below (but arenot intended by way of limitation).

Immunoprecipitation protocols generally comprise lysing a population ofcells in a lysis buffer such as RIPA buffer (1% NP40 or Triton X-100, 1%sodium deoxycholate, 0.1% SDS, 0.15 M NaCl, 0.01 M sodium phosphate atpH 7.2, 1% Trasylol) supplemented with protein phosphatase and/orprotease inhibitors (e.g., EDTA, PMSF, aprotinin, sodium vanadate),adding the antibody of interest to the cell lysate, incubating for aperiod of time (e.g., 1-4, hours) at 4° C., adding protein A and/orprotein G sepharose beads to the cell lysate, incubating for about anhour or more at 4° C., washing the beads in lysis buffer andresuspending the beads in SDS/sample buffer. The ability of the antibodyof interest to immunoprecipitate a particular antigen can be assessedby, e.g., western blot analysis. One of skill in the art would beknowledgeable as to the parameters that can be modified to increase thebinding of the antibody to an antigen and decrease the background (e.g.,pre-clearing the cell lysate with sepharose beads). For furtherdiscussion regarding immunoprecipitation protocols see, e.g., Ausubel etal., eds., (1994), Current Protocols in Molecular Biology, Vol. 1, JohnWiley & Sons, Inc., New York, section 10.16.1.

Western blot analysis generally comprises preparing protein samples,electrophoresis of the protein samples in a polyacrylamide gel (e.g.,8%-20% SDS-PAGE depending on the molecular weight of the antigen),transferring the protein sample from the polyacrylamide gel to amembrane such as nitrocellulose, PVDF or nylon, blocking the membrane inblocking solution (e.g., PBS with 3% BSA or non-fat milk), washing themembrane in washing buffer (e.g., PBS-Tween 20), blocking the membranewith primary antibody (the antibody of interest) diluted in blockingbuffer, washing the membrane in washing buffer, blocking the membranewith a secondary antibody (which recognizes the primary antibody, e.g.,an anti-human antibody) conjugated to an enzymatic substrate (e.g.,horseradish peroxidase or alkaline phosphatase) or radioactive molecule(e.g., 32P or 125I) diluted in blocking buffer, washing the membrane inwash buffer, and detecting the presence of the antigen. One of skill inthe art would be knowledgeable as to the parameters that can be modifiedto increase the signal detected and to reduce the background noise. Forfurther discussion regarding western blot protocols see, e.g., Ausubelet al, eds, (1994), Current Protocols in Molecular Biology, Vol. 1, JohnWiley & Sons, Inc., New York, section 10.8.1.

ELISAs comprise preparing antigen, coating the well of a 96 wellmicrotiter plate with the antigen, adding the antibody of interestconjugated to a detectable compound such as an enzymatic substrate(e.g., horseradish peroxidase or alkaline phosphatase) to the well andincubating for a period of time, and detecting the presence of theantigen. In ELISAs the antibody of interest does not have to beconjugated to a detectable compound; instead, a second antibody (whichrecognizes the antibody of interest) conjugated to a detectable compoundmay be added to the well. Further, instead of coating the well with theantigen, the antibody may be coated to the well. In this case, a secondantibody conjugated to a detectable compound may be added following theaddition of the antigen of interest to the coated well. One of skill inthe art would be knowledgeable as to the parameters that can be modifiedto increase the signal detected as well as other variations of ELISAsknown in the art. For further discussion regarding ELISAs see, e.g.,Ausubel et al, eds, (1994), Current Protocols in Molecular Biology, Vol.1, John Wiley & Sons, Inc., New York, section 11.2.1.

The binding affinity of an antibody to an antigen and the off-rate of anantibody-antigen interaction can be determined by competitive bindingassays. One example of a competitive binding assay is a radioimmunoassaycomprising the incubation of labeled antigen (e.g., 3H or 125I) with theantibody of interest in the presence of increasing amounts of unlabeledantigen, and the detection of the antibody bound to the labeled antigen.The affinity of the antibody of interest for a particular antigen andthe binding off-rates can be determined from the data by scatchard plotanalysis. Competition with a second antibody can also be determinedusing radioimmunoassays. In this case, the antigen is incubated withantibody of interest conjugated to a labeled compound (e.g., 3H or 125I)in the presence of increasing amounts of an unlabeled second antibody.

Antibodies of the invention may be characterized usingimmunocytochemistry methods on cells (e.g., mammalian cells, such as CHOcells) transfected with a vector enabling the expression of an antigenor with vector alone using techniques commonly known in the art.Antibodies that bind antigen transfected cells, but not vector-onlytransfected cells, are antigen specific.

Therapeutic Uses

Table 1D also provides information regarding biological activities andpreferred therapeutic uses (i.e. see, “Preferred Indications” column)for polynucleotides and polypeptides of the invention (includingantibodies, agonists, and/or antagonists thereof). Table 1D alsoprovides information regarding assays which may be used to testpolynucleotides and polypeptides of the invention (including antibodies,agonists, and/or antagonists thereof) for the corresponding biologicalactivities. The first column (“Gene No.”) provides the gene number inthe application for each clone identifier. The second column (“cDNA ATCCDeposit No:Z”) provides the unique clone identifier for each clone aspreviously described and indicated in Table 1A, Table 1B, and Table 1C.The third column (“AA SEQ ID NO:Y”) indicates the Sequence Listing SEQID Number for polypeptide sequences encoded by the corresponding cDNAclones (also as indicated in Table 1A, Table 1B, and Table 2). Thefourth column (“Biological Activity”) indicates a biological activitycorresponding to the indicated polypeptides (or polynucleotides encodingsaid polypeptides). The fifth column (“Exemplary Activity Assay”)further describes the corresponding biological activity and alsoprovides information pertaining to the various types of assays which maybe performed to test, demonstrate, or quantify the correspondingbiological activity.

The present invention is further directed to antibody-based therapieswhich involve administering antibodies of the invention to an animal,preferably a mammal, and most preferably a human, patient for treatingone or more of the disclosed diseases, disorders, or conditions.Therapeutic compounds of the invention include, but are not limited to,antibodies of the invention (including fragments, analogs andderivatives thereof as described herein) and nucleic acids encodingantibodies of the invention (including fragments, analogs andderivatives thereof and anti-idiotypic antibodies as described herein).The antibodies of the invention can be used to detect, prevent,diagnose, prognosticate, treat, and/or ameliorate diseases, disorders orconditions associated with aberrant expression and/or activity of apolypeptide of the invention, including, but not limited to,cardiovascular diseases and disorders. The treatment and/or preventionof cardiovascular diseases and disorders associated with aberrantexpression and/or activity of a polypeptide of the invention includes,but is not limited to, alleviating symptoms associated withcardiovascular diseases and disorders. Antibodies of the invention maybe provided in pharmaceutically acceptable compositions as known in theart or as described herein.

In a specific and preferred embodiment, the present invention isdirected to antibody-based therapies which involve administeringantibodies of the invention to an animal, preferably a mammal, and mostpreferably a human, patient for treating cardiovascular diseases anddisorders. Therapeutic compounds of the invention include, but are notlimited to, antibodies of the invention (e.g., antibodies directed tothe full length protein expressed on the cell surface of a mammaliancell; antibodies directed to an epitope of a polypeptide of theinvention (such as, for example, a predicted linear epitope shown inTable 1B; or a conformational epitope, including fragments, analogs andderivatives thereof as described herein) and nucleic acids encodingantibodies of the invention (including fragments, analogs andderivatives thereof and anti-idiotypic antibodies as described herein).The antibodies of the invention can be used to detect, diagnose,prevent, treat, prognosticate, and/or ameliorate cardiovasculardiseases, disorders or conditions associated with aberrant expressionand/or activity of a polypeptide of the invention. The treatment and/orprevention of cardiovascular diseases, disorders, or conditionsassociated with aberrant expression and/or activity of a polypeptide ofthe invention includes, but is not limited to, alleviating symptomsassociated with those diseases, disorders or conditions. Antibodies ofthe invention may be provided in pharmaceutically acceptablecompositions as known in the art or as described herein.

A summary of the ways in which the antibodies of the present inventionmay be used therapeutically includes binding polynucleotides orpolypeptides of the present invention locally or systemically in thebody or by direct cytotoxicity of the antibody, e.g. as mediated bycomplement (CDC) or by effector cells (ADCC). Some of these approachesare described in more detail below. Armed with the teachings providedherein, one of ordinary skill in the art will know how to use theantibodies of the present invention for diagnostic, monitoring ortherapeutic purposes without undue experimentation.

The antibodies of this invention may be advantageously utilized incombination with other monoclonal or chimeric antibodies, or withlymphokines or hematopoietic growth factors (such as, e.g., IL-2, IL-3and IL-7), for example, which serve to increase the number or activityof effector cells which interact with the antibodies.

The antibodies of the invention may be administered alone or incombination with other types of treatments (e.g., radiation therapy,chemotherapy, hormonal therapy, immunotherapy and anti-tumor agents).Generally, administration of products of a species origin or speciesreactivity (in the case of antibodies) that is the same species as thatof the patient is preferred. Thus, in a preferred embodiment, humanantibodies, fragments derivatives, analogs, or nucleic acids, areadministered to a human patient for therapy or prophylaxis.

It is preferred to use high affinity and/or potent in vivo inhibitingand/or neutralizing antibodies against polypeptides or polynucleotidesof the present invention, fragments or regions thereof, for bothimmunoassays directed to and therapy of cardiovascular diseases anddisorders related to polynucleotides or polypeptides, includingfragments thereof, of the present invention. Such antibodies, fragments,or regions, will preferably have an affinity for polynucleotides orpolypeptides of the invention, including fragments thereof. Preferredbinding affinities include those with a dissociation constant or Kd lessthan 5×10⁻² M, 10⁻² M, 5×10⁻³ M, 10⁻³ M, 5×10⁻⁴ M, 10⁻⁴M, 5×10⁻⁵M,10⁻⁵M, 5×10⁻⁶M, 10⁻⁶M, 5×10⁻⁷M, 10⁻⁷M, 5×10⁻⁸ M, 10⁻⁸M, 5×10⁻⁹ M, 10⁻⁹M, 5×10⁻¹⁰ M, 10⁻¹⁰ M, 5×10⁻¹¹ M, 10⁻¹¹ M, 5×10⁻¹² M, 10⁻¹² M, 5×10⁻¹³M, 10⁻¹³ M, 5×10⁻¹⁴ M, 10⁻¹⁴ M, 5×10⁻¹⁵ M, and 10⁻¹⁵ M.

Gene Therapy

In a specific embodiment, nucleic acids comprising sequences encodingantibodies or functional derivatives thereof, are administered to treat,inhibit or prevent a cardiovascular disease or disorder associated withaberrant expression and/or activity of a polypeptide of the invention,by way of gene therapy. Gene therapy refers to therapy performed by theadministration to a subject of an expressed or expressible nucleic acid.In this embodiment of the invention, the nucleic acids produce theirencoded protein that mediates a therapeutic effect.

Any of the methods for gene therapy available in the art can be usedaccording to the present invention. Exemplary methods are describedbelow.

For general reviews of the methods of gene therapy, see Goldspiel etal., Clinical Pharmacy 12:488-505 (1993); Wu and Wu, Biotherapy 3:87-95(1991); Tolstoshev, Ann. Rev. Pharmacol. Toxicol. 32:573-596 (1993);Mulligan, Science 260:926-932 (1993); and Morgan and Anderson, Ann. Rev.Biochem. 62:191-217 (1993); May, TIBTECH 11(5):155-215 (1993). Methodscommonly known in the art of recombinant DNA technology which can beused are described in Ausubel et al. (eds.), Current Protocols inMolecular Biology, John Wiley & Sons, NY (1993); and Kriegler, GeneTransfer and Expression, A Laboratory Manual, Stockton Press, NY (1990).

In a preferred embodiment, the compound comprises nucleic acid sequencesencoding an antibody, said nucleic acid sequences being part ofexpression vectors that express the antibody or fragments or chimericproteins or heavy or light chains thereof in a suitable host. Inparticular, such nucleic acid sequences have promoters operably linkedto the antibody coding region, said promoter being inducible orconstitutive, and, optionally, tissue-specific. In another particularembodiment, nucleic acid molecules are used in which the antibody codingsequences and any other desired sequences are flanked by regions thatpromote homologous recombination at a desired site in the genome, thusproviding for intrachromosomal expression of the antibody encodingnucleic acids (Koller and Smithies, Proc. Natl. Acad. Sci. USA86:8932-8935 (1989); Zijlstra et al., Nature 342:435438 (1989). Inspecific embodiments, the expressed antibody molecule is a single chainantibody; alternatively, the nucleic acid sequences include sequencesencoding both the heavy and light chains, or fragments thereof, of theantibody.

Delivery of the nucleic acids into a patient may be either direct, inwhich case the patient is directly exposed to the nucleic acid ornucleic acid-carrying vectors, or indirect, in which case, cells arefirst transformed with the nucleic acids in vitro, then transplantedinto the patient. These two approaches are known, respectively, as invivo or ex vivo gene therapy.

In a specific embodiment, the nucleic acid sequences are directlyadministered in vivo, where it is expressed to produce the encodedproduct. This can be accomplished by any of numerous methods known inthe art, e.g., by constructing them as part of an appropriate nucleicacid expression vector and administering it so that they becomeintracellular, e.g., by infection using defective or attenuatedretrovirals or other viral vectors (see U.S. Pat. No. 4,980,286), or bydirect injection of naked DNA, or by use of microparticle bombardment(e.g., a gene gun; Biolistic, Dupont), or coating with lipids orcell-surface receptors or transfecting agents, encapsulation inliposomes, microparticles, or microcapsules, or by administering them inlinkage to a peptide which is known to enter the nucleus, byadministering it in linkage to a ligand subject to receptor-mediatedendocytosis (see, e.g., Wu and Wu, J. Biol. Chem. 262:44294432 (1987))(which can be used to target cell types specifically expressing thereceptors), etc. In another embodiment, nucleic acid-ligand complexescan be formed in which the ligand comprises a fusogenic viral peptide todisrupt endosomes, allowing the nucleic acid to avoid lysosomaldegradation. In yet another embodiment, the nucleic acid can be targetedin vivo for cell specific uptake and expression, by targeting a specificreceptor (see, e.g., PCT Publications WO 92/06180; WO 92/22635;WO92/20316; WO93/14188, WO 93/20221). Alternatively, the nucleic acidcan be introduced intracellularly and incorporated within host cell DNAfor expression, by homologous recombination (Koller and Smithies, Proc.Natl. Acad. Sci. USA 86:8932-8935 (1989); Zijlstra et al., Nature342:435-438 (1989)).

In a specific embodiment, viral vectors that contains nucleic acidsequences encoding an antibody of the invention are used. For example, aretroviral vector can be used (see Miller et al., Meth. Enzymol.217:581-599 (1993)). These retroviral vectors contain the componentsnecessary for the correct packaging of the viral genome and integrationinto the host cell DNA. The nucleic acid sequences encoding the antibodyto be used in gene therapy are cloned into one or more vectors, whichfacilitates delivery of the gene into a patient. More detail aboutretroviral vectors can be found in Boesen et al., Biotherapy 6:291-302(1994), which describes the use of a retroviral vector to deliver themdr1 gene to hematopoietic stem cells in order to make the stem cellsmore resistant to chemotherapy. Other references illustrating the use ofretroviral vectors in gene therapy are: Clowes et al., J. Clin. Invest.93:644-651 (1994); Kiem et al., Blood 83:1467-1473 (1994); Salmons andGunzberg, Human Gene Therapy 4:129-141 (1993); and Grossman and Wilson,Curr. Opin. in Genetics and Devel. 3:110-114 (1993).

Adenoviruses are other viral vectors that can be used in gene therapy.Adenoviruses are especially attractive vehicles for delivering genes torespiratory epithelia. Adenoviruses naturally infect respiratoryepithelia where they cause a mild disease. Other targets foradenovirus-based delivery systems are liver, the central nervous system,endothelial cells, and muscle. Adenoviruses have the advantage of beingcapable of infecting non-dividing cells. Kozarsky and Wilson, CurrentOpinion in Genetics and Development 3:499-503 (1993) present a review ofadenovirus-based gene therapy. Bout et al., Human Gene Therapy 5:3-10(1994) demonstrated the use of adenovirus vectors to transfer genes tothe respiratory epithelia of rhesus monkeys. Other instances of the useof adenoviruses in gene therapy can be found in Rosenfeld et al.,Science 252:431-434 (1991); Rosenfeld et al., Cell 68:143-155 (1992);Mastrangeli et al., J. Clin. Invest. 91:225-234 (1993); PCT PublicationWO94/12649; and Wang, et al., Gene Therapy 2:775-783 (1995). In apreferred embodiment, adenovirus vectors are used.

Adeno-associated virus (AAV) has also been proposed for use in genetherapy (Walsh et al., Proc. Soc. Exp. Biol. Med. 204:289-300 (1993);U.S. Pat. No. 5,436,146).

Another approach to gene therapy involves transferring a gene to cellsin tissue culture by such methods as electroporation, lipofection,calcium phosphate mediated transfection, or viral infection. Usually,the method of transfer includes the transfer of a selectable marker tothe cells. The cells are then placed under selection to isolate thosecells that have taken up and are expressing the transferred gene. Thosecells are then delivered to a patient.

In this embodiment, the nucleic acid is introduced into a cell prior toadministration in vivo of the resulting recombinant cell. Suchintroduction can be carried out by any method known in the art,including but not limited to transfection, electroporation,microinjection, infection with a viral or bacteriophage vectorcontaining the nucleic acid sequences, cell fusion, chromosome-mediatedgene transfer, microcell-mediated gene transfer, spheroplast fusion,etc. Numerous techniques are known in the art for the introduction offoreign genes into cells (see, e.g., Loeffler and Behr, Meth. Enzymol.217:599-618 (1993); Cohen et al., Meth. Enzymol. 217:618-644 (1993);Cline, Pharmac. Ther. 29:69-92m (1985) and may be used in accordancewith the present invention, provided that the necessary developmentaland physiological functions of the recipient cells are not disrupted.The technique should provide for the stable transfer of the nucleic acidto the cell, so that the nucleic acid is expressible by the cell andpreferably heritable and expressible by its cell progeny.

The resulting recombinant cells can be delivered to a patient by variousmethods known in the art. Recombinant blood cells (e.g., hematopoieticstem or progenitor cells) are preferably administered intravenously. Theamount of cells envisioned for use depends on the desired effect,patient state, etc., and can be determined by one skilled in the art.

Cells into which a nucleic acid can be introduced for purposes of genetherapy encompass any desired, available cell type, and include but arenot limited to epithelial cells, endothelial cells, keratinocytes,fibroblasts, muscle cells, hepatocytes; blood cells such as Tlymphocytes, B lymphocytes, monocytes, macrophages, neutrophils,eosinophils, megakaryocytes, granulocytes; various stem or progenitorcells, in particular hematopoietic stem or progenitor cells, e.g., asobtained from bone marrow, umbilical cord blood, peripheral blood, fetalliver, etc.

In a preferred embodiment, the cell used for gene therapy is autologousto the patient.

In an embodiment in which recombinant cells are used in gene therapy,nucleic acid sequences encoding an antibody are introduced into thecells such that they are expressible by the cells or their progeny, andthe recombinant cells are then administered in vivo for therapeuticeffect. In a specific embodiment, stem or progenitor cells are used. Anystem and/or progenitor cells which can be isolated and maintained invitro can potentially be used in accordance with this embodiment of thepresent invention (see e.g. PCT Publication WO 94/08598; Stemple andAnderson, Cell 71:973-985 (1992); Rheinwald, Meth. Cell Bio. 21A:229(1980); and Pittelkow and Scott, Mayo Clinic Proc. 61:771 (1986)).

In a specific embodiment, the nucleic acid to be introduced for purposesof gene therapy comprises an inducible promoter operably linked to thecoding region, such that expression of the nucleic acid is controllableby the presence or absence of an appropriate inducer of transcription.

Demonstration of Therapeutic or Prophylactic Activity

The compounds or pharmaceutical compositions of the invention arepreferably tested in vitro, and then in vivo for the desired therapeuticor prophylactic activity, prior to use in humans. For example, in vitroassays to demonstrate the therapeutic or prophylactic utility of acompound or pharmaceutical composition include, the effect of a compoundon a cell line or a patient tissue sample. The effect of the compound orcomposition on the cell line and/or tissue sample can be determinedutilizing techniques known to those of skill in the art including, butnot limited to, rosette formation assays and cell lysis assays. Inaccordance with the invention, in vitro assays which can be used todetermine whether administration of a specific compound is indicated,include in vitro cell culture assays in which a patient tissue sample isgrown in culture, and exposed to or otherwise administered a compound,and the effect of such compound upon the tissue sample is observed.

Therapeutic/Prophylactic Administration and Composition

The invention provides methods of treatment, inhibition and prophylaxisby administration to a subject of an effective amount of a compound orpharmaceutical composition of the invention, preferably a polypeptide orantibody of the invention. In a preferred embodiment, the compound issubstantially purified (e.g., substantially free from substances thatlimit its effect or produce undesired side-effects). The subject ispreferably an animal, including but not limited to animals such as cows,pigs, horses, chickens, cats, dogs, etc., and is preferably a mammal,and most preferably human.

Formulations and methods of administration that can be employed when thecompound comprises a nucleic acid or an immunoglobulin are describedabove; additional appropriate formulations and routes of administrationcan be selected from among those described herein below.

Various delivery systems are known and can be used to administer acompound of the invention, e.g., encapsulation in liposomes,microparticles, microcapsules, recombinant cells capable of expressingthe compound, receptor-mediated endocytosis (see, e.g., Wu and Wu, J.Biol. Chem. 262:4429-4432 (1987)), construction of a nucleic acid aspart of a retroviral or other vector, etc. Methods of introductioninclude but are not limited to intradermal, intramuscular,intraperitoneal, intravenous, subcutaneous, intranasal, epidural, andoral routes. The compounds or compositions may be administered by anyconvenient route, for example by infusion or bolus injection, byabsorption through epithelial or mucocutaneous linings (e.g., oralmucosa, rectal and intestinal mucosa, etc.) and may be administeredtogether with other biologically active agents. Administration can besystemic or local. In addition, it may be desirable to introduce thepharmaceutical compounds or compositions of the invention into thecentral nervous system by any suitable route, including intraventricularand intrathecal injection; intraventricular injection may be facilitatedby an intraventricular catheter, for example, attached to a reservoir,such as an Ommaya reservoir. Pulmonary administration can also beemployed, e.g., by use of an inhaler or nebulizer, and formulation withan aerosolizing agent.

In a specific embodiment, it may be desirable to administer thepharmaceutical compounds or compositions of the invention locally to thearea in need of treatment; this may be achieved by, for example, and notby way of limitation, local infusion during surgery, topicalapplication, e.g., in conjunction with a wound dressing after surgery,by injection, by means of a catheter, by means of a suppository, or bymeans of an implant, said implant being of a porous, non-porous, orgelatinous material, including membranes, such as sialastic membranes,or fibers. Preferably, when administering a protein, including anantibody, of the invention, care must be taken to use materials to whichthe protein does not absorb.

In another embodiment, the compound or composition can be delivered in avesicle, in particular a liposome (see Langer, Science 249:1527-1533(1990); Treat et al., in Liposomes in the Therapy of Infectious Diseaseand Cancer, Lopez-Berestein and Fidler (eds.), Liss, New York, pp.353-365 (1989); Lopez-Berestein, ibid., pp.317-327; see generally ibid.)

In yet another embodiment, the compound or composition can be deliveredin a controlled release system. In one embodiment, a pump may be used(see Langer, supra; Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987);Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med.321:574 (1989)). In another embodiment, polymeric materials can be used(see Medical Applications of Controlled Release, Langer and Wise (eds.),CRC Pres., Boca Raton, Fla. (1974); Controlled Drug Bioavailability,Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, NewYork (1984); Ranger and Peppas, J., Macromol. Sci. Rev. Macromol. Chem.23:61 (1983); see also Levy et al., Science 228:190 (1985); During etal., Ann. Neurol. 25:351 (1989); Howard et al., J. Neurosurg. 71:105(1989)). In yet another embodiment, a controlled release system can beplaced in proximity of the therapeutic target, e.g., the brain, thusrequiring only a fraction of the systemic dose (see, e.g., Goodson, inMedical Applications of Controlled Release, supra, vol. 2, pp. 115-138(1984)).

Other controlled release systems are discussed in the review by Langer(Science 249:1527-1533 (1990)).

In a specific embodiment where the compound of the invention is anucleic acid encoding a protein, the nucleic acid can be administered invivo to promote expression of its encoded protein, by constructing it aspart of an appropriate nucleic acid expression vector and administeringit so that it becomes intracellular, e.g., by use of a retroviral vector(see U.S. Pat. No. 4,980,286), or by direct injection, or by use ofmicroparticle bombardment (e.g., a gene gun; Biolistic, Dupont), orcoating with lipids or cell-surface receptors or transfecting agents, orby administering it in linkage to a homeobox-like peptide which is knownto enter the nucleus (see e.g., Joliot et al., Proc. Natl. Acad. Sci.USA 88:1864-1868 (1991)), etc. Alternatively, a nucleic acid can beintroduced intracellularly and incorporated within host cell DNA forexpression, by homologous recombination.

The present invention also provides pharmaceutical compositions. Suchcompositions comprise a therapeutically effective amount of a compound,and a pharmaceutically acceptable carrier. In a specific embodiment, theterm “pharmaceutically acceptable” means approved by a regulatory agencyof the Federal or a state government or listed in the U.S. Pharmacopeiaor other generally recognized pharmacopeia for use in animals, and moreparticularly in humans. The term “carrier” refers to a diluent,adjuvant, excipient, or vehicle with which the therapeutic isadministered. Such pharmaceutical carriers can be sterile liquids, suchas water and oils, including those of petroleum, animal, vegetable orsynthetic origin, such as peanut oil, soybean oil, mineral oil, sesameoil and the like. Water is a preferred carrier when the pharmaceuticalcomposition is administered intravenously. Saline solutions and aqueousdextrose and glycerol solutions can also be employed as liquid carriers,particularly for injectable solutions. Suitable pharmaceuticalexcipients include starch, glucose, lactose, sucrose, gelatin, malt,rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate,talc, sodium chloride, dried skim milk, glycerol, propylene, glycol,water, ethanol and the like. The composition, if desired, can alsocontain minor amounts of wetting or emulsifying agents, or pH bufferingagents. These compositions can take the form of solutions, suspensions,emulsion, tablets, pills, capsules, powders, sustained-releaseformulations' and the like. The composition can be formulated as asuppository, with traditional binders and carriers such astriglycerides. Oral formulation can include standard carriers such aspharmaceutical grades of mannitol, lactose, starch, magnesium stearate,sodium saccharine, cellulose, magnesium carbonate, etc. Examples ofsuitable pharmaceutical carriers are described in “Remington'sPharmaceutical Sciences” by E. W. Martin. Such compositions will containa therapeutically effective amount of the compound, preferably inpurified form, together with a suitable amount of carrier so as toprovide the form for proper administration to the patient. Theformulation should suit the mode of administration.

In a preferred embodiment, the composition is formulated in accordancewith routine procedures as a pharmaceutical composition adapted forintravenous administration to human beings. Typically, compositions forintravenous administration are solutions in sterile isotonic aqueousbuffer. Where necessary, the composition may also include a solubilizingagent and a local anesthetic such as lignocaine to ease pain at the siteof the injection. Generally, the ingredients are supplied eitherseparately or mixed together in unit dosage form, for example, as a drylyophilized powder or water free concentrate in a hermetically sealedcontainer such as an ampoule or sachette indicating the quantity ofactive agent. Where the composition is to be administered by infusion,it can be dispensed with an infusion bottle containing sterilepharmaceutical grade water or saline. Where the composition isadministered by injection, an ampoule of sterile water for injection orsaline can be provided so that the ingredients may be mixed prior toadministration.

The compounds of the invention can be formulated as neutral or saltforms. Pharmaceutically acceptable salts include those formed withanions such as those derived from hydrochloric, phosphoric, acetic,oxalic, tartaric acids, etc., and those formed with cations such asthose derived from sodium, potassium, ammonium, calcium, ferrichydroxides, isopropylamine, triethylamine, 2-ethylamino ethanol,histidine, procaine, etc.

The amount of the compound of the invention which will be effective inthe treatment, inhibition and prevention of a disease or disorderassociated with aberrant expression and/or activity of a polypeptide ofthe invention can be determined by standard clinical techniques. Inaddition, in vitro assays may optionally be employed to help identifyoptimal dosage ranges. The precise dose to be employed in theformulation will also depend on the route of administration, and theseriousness of the disease or disorder, and should be decided accordingto the judgment of the practitioner and each patient's circumstances.Effective doses may be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

For antibodies, the dosage administered to a patient is typically 0.1mg/kg to 100 mg/kg of the patient's body weight. Preferably, the dosageadministered to a patient is between 0.1 mg/kg and 20 mg/kg of thepatient's body weight, more preferably 1 mg/kg to 10 mg/kg of thepatient's body weight. Generally, human antibodies have a longerhalf-life within the human body than antibodies from other species dueto the immune response to the foreign polypeptides. Thus, lower dosagesof human antibodies and less frequent administration is often possible.Further, the dosage and frequency of administration of antibodies of theinvention may be reduced by enhancing uptake and tissue penetration(e.g., into the brain) of the antibodies by modifications such as, forexample, lipidation.

The invention also provides a pharmaceutical pack or kit comprising oneor more containers filled with one or more of the ingredients of thepharmaceutical compositions of the invention. Optionally associated withsuch container(s) can be a notice in the form prescribed by agovernmental agency regulating the manufacture, use or sale ofpharmaceuticals or biological products, which notice reflects approvalby the agency of manufacture, use or sale for human administration.

Diagnosis and Imaging

Labeled antibodies, and derivatives and analogs thereof, whichspecifically bind to a polypeptide of interest can be used fordiagnostic purposes to detect, diagnose, prognosticate, or monitorcardiovascular diseases, disorders, and/or conditions associated withthe aberrant expression and/or activity of a polypeptide of theinvention. The invention provides for the detection of aberrantexpression of a polypeptide of interest, comprising (a) assaying theexpression of the polypeptide of interest in cells or body fluid of anindividual using one or more antibodies specific to the polypeptideinterest and (b) comparing the level of gene expression with a standardgene expression level, whereby an increase or decrease in the assayedpolypeptide gene expression level compared to the standard expressionlevel is indicative of aberrant expression.

The invention provides a diagnostic assay for diagnosing acardiovascular disease or disorder, comprising (a) assaying theexpression of the polypeptide of interest in cells or body fluid of anindividual using one or more antibodies specific to the polypeptideinterest and (b) comparing the level of gene expression with a standardgene expression level, whereby an increase or decrease in the assayedpolypeptide gene expression level compared to the standard expressionlevel is indicative of a particular cardiovascular disease or disorder.With respect to cancers of the cardiovascular system, the presence of arelatively high amount of transcript in biopsied tissue from anindividual may indicate a predisposition for the development of thedisease, or may provide a means for detecting the disease prior to theappearance of actual clinical symptoms. A more definitive diagnosis ofthis type may allow health professionals to employ preventative measuresor aggressive treatment earlier thereby preventing the development orfurther progression of the cancer of the cardiovascular system.

Antibodies of the invention can be used to assay protein levels in abiological sample using classical immunohistological methods known tothose of skill in the art (e.g., see Jalkanen et al., J. Cell. Biol.101:976-985 (1985); Jalkanen et al., J. Cell. Biol. 105:3087-3096(1987)). Other antibody-based methods useful for detecting protein geneexpression include immunoassays, such as the enzyme linked immunosorbentassay (ELISA) and the radioimmunoassay (RIA). Suitable antibody assaylabels are known in the art and include enzyme labels, such as, glucoseoxidase; radioisotopes, such as iodine (125I, 121I), carbon (14C),sulfur (35S), tritium (3H, indium (112In), and technetium (99Tc);luminescent labels, such as luminol; and fluorescent labels, such asfluorescein and rhodamine, and biotin.

One facet of the invention is the detection and diagnosis of a diseaseor disorder associated with aberrant expression of a polypeptide ofinterest in an animal, preferably a mammal and most preferably a human.In one embodiment, diagnosis comprises: a) administering (for example,parenterally, subcutaneously, or intraperitoneally) to a subject aneffective amount of a labeled molecule which specifically binds to thepolypeptide of interest, b) waiting for a time interval following theadministering for permitting the labeled molecule to preferentiallyconcentrate at sites in the subject where the polypeptide is expressed(and for unbound labeled molecule to be cleared to background level); c)determining background level; and d) detecting the labeled molecule inthe subject, such that detection of labeled molecule above thebackground level indicates that the subject has a particular disease ordisorder associated with aberrant expression of the polypeptide ofinterest. Background level can be determined by various methodsincluding, comparing the amount of labeled molecule detected to astandard value previously determined for a particular system.

It will be understood in the art that the size of the subject and theimaging system used will determine the quantity of imaging moiety neededto produce diagnostic images. In the case of a radioisotope moiety, fora human subject, the quantity of radioactivity injected will normallyrange from about 5 to 20 millicuries of 99 mTc. The labeled antibody orantibody fragment will then preferentially accumulate at the location ofcells which contain the specific protein. In vivo tumor imaging isdescribed in S. W. Burchiel et al., “Immunopharmacokinetics ofRadiolabeled Antibodies and Their Fragments.” (Chapter 13 in TumorImaging: The Radiochemical Detection of Cancer, S. W. Burchiel and B. A.Rhodes, eds., Masson Publishing Inc. (1982)).

Depending on several variables, including the type of label used and themode of administration, the time interval following the administrationfor permitting the labeled molecule to preferentially concentrate atsites in the subject and for unbound labeled molecule to be cleared tobackground level is 6 to 48 hours or 6 to 24 hours or 6 to 12 hours. Inanother embodiment the time interval following administration is 5 to 20days or 5 to 10 days.

In an embodiment, monitoring of the disease or disorder is carried outby repeating the method for diagnosing the disease or disease, forexample, one month after initial diagnosis, six months after initialdiagnosis, one year after initial diagnosis, etc.

Presence of the labeled molecule can be detected in the patient usingmethods known in the art for in vivo scanning. These methods depend uponthe type of label used. Skilled artisans will be able to determine theappropriate method for detecting a particular label. Methods and devicesthat may be used in the diagnostic methods of the invention include, butare not limited to, computed tomography (CT), whole body scan such asposition emission tomography (PAT), magnetic resonance imaging (MRI, andsonography.

In a specific embodiment, the molecule is labeled with a radioisotopeand is detected in The patient using a radiation responsive surgicalinstrument (Thurston et al., U.S. Pat. No. 5,441,050). In anotherembodiment, the molecule is labeled with a fluorescent compound and isdetected in the patient using a fluorescence responsive scanninginstrument. In another embodiment, the molecule is labeled with apositron emitting metal and is detected in the patent using positronemission-tomography. In yet another embodiment, the molecule is labeledwith a paramagnetic label and is detected in a patient using magneticresonance imaging (MRI).

Kits

The present invention provides kits that can be used in the abovemethods. In one embodiment, a kit comprises an antibody of theinvention, preferably a purified antibody, in one or more containers. Ina specific embodiment, the kits of the present invention contain asubstantially isolated polypeptide comprising an epitope which isspecifically immunoreactive with an antibody included in the kit.Preferably, the kits of the present invention further comprise a controlantibody which does not react with the polypeptide of interest. Inanother specific embodiment, the kits of the present invention contain ameans for detecting the binding of an antibody to a polypeptide ofinterest (e.g., the antibody may be conjugated to a detectable substratesuch as a fluorescent compound, an enzymatic substrate, a radioactivecompound or a luminescent compound, or a second antibody whichrecognizes the first antibody may be conjugated to a detectablesubstrate).

In another specific embodiment of the present invention, the kit is adiagnostic kit for use in screening serum containing antibodies specificagainst proliferative and/or cancerous polynucleotides and polypeptides.Such a kit may include a control antibody that does not react with thepolypeptide of interest. Such a kit may include a substantially isolatedpolypeptide antigen comprising an epitope which is specificallyimmunoreactive with at least one anti-polypeptide antigen antibody.Further, such a kit includes means for detecting the binding of saidantibody to the antigen (e.g., the antibody may be conjugated to afluorescent compound such as fluorescein or rhodamine which can bedetected by flow cytometry). In specific embodiments, the kit mayinclude a recombinantly produced or chemically synthesized polypeptideantigen. The polypeptide antigen of the kit may also be attached to asolid support.

In a more specific embodiment the detecting means of the above-describedkit includes a solid support to which said polypeptide antigen isattached. Such a kit may also include a non-attached reporter-labeledanti-human antibody. In this embodiment, binding of the antibody to thepolypeptide antigen can be detected by binding of the saidreporter-labeled antibody.

In an additional embodiment, the invention includes a diagnostic kit foruse in screening serum containing antigens of the polypeptide of theinvention. The diagnostic kit includes a substantially isolated antibodyspecifically immunoreactive with polypeptide or polynucleotide antigens,and means for detecting the binding of the polynucleotide or polypeptideantigen to the antibody. In one embodiment, the antibody is attached toa solid support. In a specific embodiment, the antibody may be amonoclonal antibody. The detecting means of the kit may include asecond, labeled monoclonal antibody. Alternatively, or in addition, thedetecting means may include a labeled, competing antigen.

In one diagnostic configuration, test serum is reacted with a solidphase reagent having a surface-bound antigen obtained by the methods ofthe present invention. After binding with specific antigen antibody tothe reagent and removing unbound serum components by washing, thereagent is reacted with reporter-labeled anti-human antibody to bindreporter to the reagent in proportion to the amount of boundanti-antigen antibody on the solid support. The reagent is again washedto remove unbound labeled antibody, and the amount of reporterassociated with the reagent is determined. Typically, the reporter is anenzyme which is detected by incubating the solid phase in the presenceof a suitable fluorometric, luminescent or colorimetric substrate(Sigma, St. Louis, Mo.).

The solid surface reagent in the above assay is prepared by knowntechniques for attaching protein material to solid support material,such as polymeric beads, dip sticks, 96-well plate or filter material.These attachment methods generally include non-specific adsorption ofthe protein to the support or covalent attachment of the protein,typically through a free amine group, to a chemically reactive group onthe solid support, such as an activated carboxyl, hydroxyl, or aldehydegroup. Alternatively, streptavidin coated plates can be used inconjunction with biotinylated antigen(s).

Thus, the invention provides an assay system or kit for carrying outthis diagnostic method. The kit generally includes a support withsurface-bound recombinant antigens, and a reporter-labeled anti-humanantibody for detecting surface-bound anti-antigen antibody.

Uses of the Polynucleotides

Each of the polynucleotides identified herein can be used in numerousways as reagents. The following description should be consideredexemplary and utilizes known techniques.

The polynucleotides of the present invention are useful for chromosomeidentification. There exists an ongoing need to identify new chromosomemarkers, since few chromosome marking reagents, based on actual sequencedata (repeat polymorphisms), are presently available. Each sequence isspecifically targeted to and can hybridize with a particular location onan individual human chromosome, thus each polynucleotide of the presentinvention can routinely be used as a chromosome marker using techniquesknown in the art. Table 1B, column 9 provides the chromosome location ofsome of the polynucleotides of the invention.

Briefly, sequences can be mapped to chromosomes by preparing PCR primers(preferably at least 15 bp (e.g., 15-25 bp) from the sequences shown inSEQ ID NO:X. Primers can optionally be selected using computer analysisso that primers do not span more than one predicted exon in the genomicDNA. These primers are then used for PCR screening of somatic cellhybrids containing individual human chromosomes. Only those hybridscontaining the human gene corresponding to SEQ ID NO:X will yield anamplified fragment.

Similarly, somatic hybrids provide a rapid method of PCR mapping thepolynucleotides to particular chromosomes. Three or more clones can beassigned per day using a single thermal cycler. Moreover,sublocalization of the polynucleotides can be achieved with panels ofspecific chromosome fragments. Other gene mapping strategies that can beused include in situ hybridization, prescreening with labeledflow-sorted chromosomes, preselection by hybridization to constructchromosome specific-cDNA libraries, and computer mapping techniques(See, e.g., Shuler, Trends Biotechnol 16:456459 (1998) which is herebyincorporated by reference in its entirety).

Precise chromosomal location of the polynucleotides can also be achievedusing fluorescence in situ hybridization (FISH) of a metaphasechromosomal spread. This technique uses polynucleotides as short as 500or 600 bases; however, polynucleotides 2,0004,000 bp are preferred. Fora review of this technique, see Verma et al., “Human Chromosomes: aManual of Basic Techniques,” Pergamon Press, New York (1988).

For chromosome mapping, the polynucleotides can be used individually (tomark a single chromosome or a single site on that chromosome) or inpanels (for marking multiple sites and/or multiple chromosomes).

Thus, the present invention also provides a method for chromosomallocalization which involves (a) preparing PCR primers from thepolynucleotide sequences in Table 1B and/or Table 2 and SEQ ID NO:X and(b) screening somatic cell hybrids containing individual chromosomes.

The polynucleotides of the present invention would likewise be usefulfor radiation hybrid mapping, HAPPY mapping, and long range restrictionmapping. For a review of these techniques and others known in the art,see, e.g. Dear, “Genome Mapping: A Practical Approach,” IRL Press atOxford University Press, London (1997); Aydin, J. Mol. Med. 77:691-694(1999); Hacia et al., Mol. Psychiatry 3:483-492 (1998); Herrick et al.,Chromosome Res. 7:409-423 (1999); Hamilton et al., Methods Cell Biol.62:265-280 (2000); and/or Ott, J. Hered. 90:68-70 (1999) each of whichis hereby incorporated by reference in its entirety.

Once a polynucleotide has been mapped to a precise chromosomal location,the physical position of the polynucleotide can be used in linkageanalysis. Linkage analysis establishes coinheritance between achromosomal location and presentation of a particular disease. (Diseasemapping data are found, for example, in V. McKusick, MendelianInheritance in Man (available on line through Johns Hopkins UniversityWelch Medical Library)). Table 1B provides an OMIM referenceidentification number of diseases associated with the cytologic banddisclosed in Table 1B, as determined using techniques described hereinand by reference to Table 5. Assuming 1 megabase mapping resolution andone gene per 20 kb, a cDNA precisely localized to a chromosomal regionassociated with the disease could be one of 50-500 potential causativegenes.

Thus, once coinheritance is established, differences in a polynucleotideof the invention and the corresponding gene between affected andunaffected individuals can be examined. First, visible structuralalterations in the chromosomes, such as deletions or translocations, areexamined in chromosome spreads or by PCR. If no structural alterationsexist, the presence of point mutations are ascertained. Mutationsobserved in some or all affected individuals, but not in normalindividuals, indicates that the mutation may cause the disease. However,complete sequencing of the polypeptide and the corresponding gene fromseveral normal individuals is required to distinguish the mutation froma polymorphism. If a new polymorphism is identified, this polymorphicpolypeptide can be used for further linkage analysis.

Furthermore, increased or decreased expression of the gene in affectedindividuals as compared to unaffected individuals can be assessed usingthe polynucleotides of the invention. Any of these alterations (alteredexpression, chromosomal rearrangement, or mutation) can be used as adiagnostic or prognostic marker. Diagnostic and prognostic methods, kitsand reagents encompassed by the present invention are briefly describedbelow and more thoroughly elsewhere herein (see e.g., the sectionslabeled “Antibodies”, “Diagnostic Assays”, and “Methods for DetectingDiseases”).

Thus, the invention also provides a diagnostic method useful duringdiagnosis of a disorder, involving measuring the expression level ofpolynucleotides of the present invention in cells or body fluid from anindividual and comparing the measured gene expression level with astandard level of polynucleotide expression level, whereby an increaseor decrease in the gene expression level compared to the standard isindicative of a disorder. Additional non-limiting examples of diagnosticmethods encompassed by the present invention are more thoroughlydescribed elsewhere herein (see, e.g., Example 12).

In still another embodiment, the invention includes a kit for analyzingsamples for the presence of proliferative and/or cancerouspolynucleotides derived from a test subject. In a general embodiment,the kit includes at least one polynucleotide probe containing anucleotide sequence that will specifically hybridize with apolynucleotide of the invention and a suitable container. In a specificembodiment, the kit includes two polynucleotide probes defining aninternal region of the polynucleotide of the invention, where each probehas one strand containing a 31′mer-end internal to the region. In afurther embodiment, the probes may be useful as primers for polymerasechain reaction amplification.

Where a diagnosis of a related disorder, including, for example,diagnosis of a tumor, has already been made according to conventionalmethods, the present invention is useful as a prognostic indicator,whereby patients exhibiting enhanced or depressed polynucleotide of theinvention expression will experience a worse clinical outcome relativeto patients expressing the gene at a level nearer the standard level.

By “measuring the expression level of polynucleotides of the invention”is intended qualitatively or quantitatively measuring or estimating thelevel of the polypeptide of the invention or the level of the mRNAencoding the polypeptide of the invention in a first biological sampleeither directly (e.g., by determining or estimating absolute proteinlevel or mRNA level) or relatively (e.g., by comparing to thepolypeptide level or mRNA level in a second biological sample).Preferably, the polypeptide level or mRNA level in the first biologicalsample is measured or estimated and compared to a standard polypeptidelevel or mRNA level, the standard being taken from a second biologicalsample obtained from an individual not having the related disorder orbeing determined by averaging levels from a population of individualsnot having a related disorder. As will be appreciated in the art, once astandard polypeptide level or mRNA level is known, it can be usedrepeatedly as a standard for comparison.

By “biological sample” is intended any biological sample obtained froman individual, body fluid, cell line, tissue culture, or other sourcewhich contains polypeptide of the present invention or the correspondingmRNA. As indicated, biological samples include body fluids (such assemen, lymph, vaginal pool, sera, plasma, urine, synovial fluid andspinal fluid) which contain the polypeptide of the present invention,and tissue sources found to express the polypeptide of the presentinvention. Methods for obtaining tissue biopsies and body fluids frommammals are well known in the art. Where the biological sample is toinclude mRNA, a tissue biopsy is the preferred source.

The method(s) provided above may preferably be applied in a diagnosticmethod and/or kits in which polynucleotides and/or polypeptides of theinvention are attached to a solid support. In one exemplary method, thesupport may be a “gene chip” or a “biological chip” as described in U.S.Pat. Nos. 5,837,832, 5,874,219, and 5,856,174. Further, such a gene chipwith polynucleotides of the invention attached may be used to identifypolymorphisms between the isolated polynucleotide sequences of theinvention, with polynucleotides isolated from a test subject. Theknowledge of such polymorphisms (i.e. their location, as well as, theirexistence) would be beneficial in identifying disease loci for manydisorders, such as for example, in neural disorders, immune systemdisorders, muscular disorders, reproductive disorders, gastrointestinaldisorders, pulmonary disorders, digestive disorders, metabolicdisorders, cardiovascular disorders, renal disorders, proliferativedisorders, and/or cancerous diseases and conditions. Such a method isdescribed in U.S. Pat. Nos. 5,858,659 and 5,856,104. The US Patentsreferenced supra are hereby incorporated by reference in their entiretyherein.

The present invention encompasses polynucleotides of the presentinvention that are chemically synthesized, or reproduced as peptidenucleic acids (PNA), or according to other methods known in the art. Theuse of PNAs would serve as the preferred form if the polynucleotides ofthe invention are incorporated onto a solid support, or gene chip. Forthe purposes of the present invention, a peptide nucleic acid (PNA) is apolyanide type of DNA analog and the monomeric units for adenine,guanine, thymine and cytosine are available commercially (PerceptiveBiosystems). Certain components of DNA, such as phosphorus, phosphorusoxides, or deoxyribose derivatives, are not present in PNAs. Asdisclosed by Nielsen et al., Science 254, 1497 (1991); and Egholm etal., Nature 365, 666 (1993), PNAs bind specifically and tightly tocomplementary DNA strands and are not degraded by nucleases. In fact,PNA binds more strongly to DNA than DNA itself does. This is probablybecause there is no electrostatic repulsion between the two strands, andalso the polyamide backbone is more flexible. Because of this, PNA/DNAduplexes bind under a wider range of stringency conditions than DNA/DNAduplexes, making it easier to perform multiplex hybridization. Smallerprobes can be used than with DNA due to the strong binding. In addition,it is more likely that single base mismatches can be determined withPNA/DNA hybridization because a single mismatch in a PNA/DNA 15-merlowers the melting point (T.sub.m) by 8°-20° C., vs. 4°-16° C. for theDNA/DNA 15-mer duplex. Also, the absence of charge groups in PNA meansthat hybridization can be done at low ionic strengths and reducepossible interference by salt during the analysis.

The compounds of the present invention have uses which include, but arenot limited to, detecting cancer in mammals. In particular the inventionis useful during diagnosis of pathological cell proliferative neoplasiaswhich include, but are not limited to: acute myelogenous leukemiasincluding acute monocytic leukemia, acute myeloblastic leukemia, acutepromyelocytic leukemia, acute myelomonocytic leukemia, acuteerythroleukemia, acute megakaryocytic leukemia, and acuteundifferentiated leukemia, etc.; and chronic myelogenous leukemiasincluding chronic myelomonocytic leukemia, chronic granulocyticleukemia, etc. Preferred mammals include monkeys, apes, cats, dogs,cows, pigs, horses, rabbits and humans. Particularly preferred arehumans.

Pathological cell proliferative disorders are often associated withinappropriate activation of proto-oncogenes. (Gelmann, E. P. et al.,“The Etiology of Acute Leukemia: Molecular Genetics and Viral Oncology,”in Neoplastic Diseases of the Blood, Vol 1., Wiernik, P. H. et al. eds.,161-182 (1985)). Neoplasias are now believed to result from thequalitative alteration of a normal cellular gene product, or from thequantitative modification of gene expression by insertion into thechromosome of a viral sequence, by chromosomal translocation of a geneto a more actively transcribed region, or by some other mechanism(Gelmann et al., supra) It is likely that mutated or altered expressionof specific genes is involved in the pathogenesis of some leukemias,among other tissues and cell types. (Gelmann et al., supra) Indeed, thehuman counterparts of the oncogenes involved in some animal neoplasiashave been amplified or translocated in some cases of human leukemia andcarcinoma. (Gelmann et al., supra)

For example, c-myc expression is highly amplified in the non-lymphocyticleukemia cell line HL-60. When HL-60 cells are chemically induced tostop proliferation, the level of c-myc is found to be downregulated.(International Publication Number WO 91/15580). However, it has beenshown that exposure of HL-60 cells to a DNA construct that iscomplementary to the 5′ end of c-myc or c-myb blocks translation of thecorresponding mRNAs which down-regulates expression of the c-myc orc-myb proteins and causes arrest of cell proliferation anddifferentiation of the treated cells. (International Publication NumberWO 91/15580; Wickstrom et al., Proc. Natl. Acad. Sci. 85:1028 (1988);Anfossi et al., Proc. Natl. Acad. Sci. 86:3379 (1989)). However, theskilled artisan would appreciate the present invention's usefulness isnot be limited to treatment, prevention, and/or prognosis ofproliferative disorders of cells and tissues of hematopoietic origin, inlight of the numerous cells and cell types of varying origins which areknown to exhibit proliferative phenotypes.

In addition to the foregoing, a polynucleotide of the present inventioncan be used to control gene expression through triple helix formation orthrough antisense DNA or RNA. Antisense techniques are discussed, forexample, in Okano, J. Neurochem. 56: 560 (1991); “Oligodeoxynucleotidesas Antisense Inhibitors of Gene Expression, CRC Press, Boca Raton, Fla.(1988). Triple helix formation is discussed in, for instance Lee et al.,Nucleic Acids Research 6: 3073 (1979); Cooney et al., Science 241: 456(1988); and Dervan et al., Science 251: 1360 (1991). Both methods relyon binding of the polynucleotide to a complementary DNA or RNA. Forthese techniques, preferred polynucleotides are usually oligonucleotides20 to 40 bases in length and complementary to either the region of thegene involved in transcription (triple helix—see Lee et al., Nucl. AcidsRes. 6:3073 (1979); Cooney et al., Science 241:456 (1988); and Dervan etal., Science 251:1360 (1991)) or to the mRNA itself (antisense—Okano, J.Neurochem 56:560 (1991); Oligodeoxy-nucleotides as Antisense Inhibitorsof Gene Expression, CRC Press, Boca Raton, Fla. (1988)). Triple helixformation optimally results in a shut-off of RNA transcription from DNA,while antisense RNA hybridization blocks translation of an mRNA moleculeinto polypeptide. The oligonucleotide described above can also bedelivered to cells such that the antisense RNA or DNA may be expressedin vivo to inhibit production of polypeptide of the present inventionantigens. Both techniques are effective in model systems, and theinformation disclosed herein can be used to design antisense or triplehelix polynucleotides in an effort to treat disease, and in particular,for the treatment of proliferative diseases and/or conditions.Non-limiting antisense and triple helix methods encompassed by thepresent invention are more thoroughly described elsewhere herein (see,e.g., the section labeled “Antisense and Ribozyme (Antagonists)”).

Polynucleotides of the present invention are also useful in genetherapy. One goal of gene therapy is to insert a normal gene into anorganism having a defective gene, in an effort to correct the geneticdefect. The polynucleotides disclosed in the present invention offer ameans of targeting such genetic defects in a highly accurate manner.Another goal is to insert a new gene that was not present in the hostgenome, thereby producing a new trait in the host cell. Additionalnon-limiting examples of gene therapy methods encompassed by the presentinvention are more thoroughly described elsewhere herein (see, e.g., thesections labeled “Gene Therapy Methods”, and Examples 16, 17 and 18).

The polynucleotides are also useful for identifying individuals fromminute biological samples. The United States military, for example, isconsidering the use of restriction fragment length polymorphism (RFLP)for identification of its personnel. In this technique, an individual'sgenomic DNA is digested with one or more restriction enzymes, and probedon a Southern blot to yield unique bands for identifying personnel. Thismethod does not suffer from the current limitations of “Dog Tags” whichcan be lost, switched, or stolen, making positive identificationdifficult. The polynucleotides of the present invention can be used asadditional DNA markers for RFLP.

The polynucleotides of the present invention can also be used as analternative to RFLP, by determining the actual base-by-base DNA sequenceof selected portions of an individual's genome. These sequences can beused to prepare PCR primers for amplifying and isolating such selectedDNA, which can then be sequenced. Using this technique, individuals canbe identified because each individual will have a unique set of DNAsequences. Once an unique ID database is established for an individual,positive identification of that individual, living or dead, can be madefrom extremely small tissue samples.

Forensic biology also benefits from using DNA-based identificationtechniques as disclosed herein. DNA sequences taken from very smallbiological samples such as tissues, e.g., hair or skin, or body fluids,e.g., blood, saliva, semen, synovial fluid, amniotic fluid, breast milk,lymph, pulmonary sputum or surfactant, urine, fecal matter, etc., can beamplified using PCR. In one prior art technique, gene sequencesamplified from polymorphic loci, such as DQa class II HLA gene, are usedin forensic biology to identify individuals. (Erlich, H., PCRTechnology, Freeman and Co. (1992)). Once these specific polymorphicloci are amplified, they are digested with one or more restrictionenzymes, yielding an identifying set of bands on a Southern blot probedwith DNA corresponding to the DQa class II HLA gene. Similarly,polynucleotides of the present invention can be used as polymorphicmarkers for forensic purposes.

There is also a need for reagents capable of identifying the source of aparticular tissue. Such need arises, for example, in forensics whenpresented with tissue of unknown origin. Appropriate reagents cancomprise, for example, DNA probes or primers prepared from the sequencesof the present invention, specific to tissues, including but not limitedto those shown in Table 1B. Panels of such reagents can identify tissueby species and/or by organ type. In a similar fashion, these reagentscan be used to screen tissue cultures for contamination. Additionalnon-limiting examples of such uses are further described herein.

The polynucleotides of the present invention are also useful ashybridization probes for differential identification of the tissue(s) orcell type(s) present in a biological sample. Similarly, polypeptides andantibodies directed to polypeptides of the present invention are usefulto provide immunological probes for differential identification of thetissue(s) (e.g., immunohistochemistry assays) or cell type(s) (e.g.,immunocytochemistry assays). In addition, for a number of disorders ofthe above tissues or cells, significantly higher or lower levels of geneexpression of the polynucleotides/polypeptides of the present inventionmay be detected in certain tissues (e.g., tissues expressingpolypeptides and/or polynucleotides of the present invention, forexample, those disclosed in Table 1B, and/or cancerous and/or woundedtissues) or bodily fluids (e.g., semen, lymph, vaginal pool, serum,plasma, urine, synovial fluid or spinal fluid) taken from an individualhaving such a disorder, relative to a “standard” gene expression level,i.e., the expression level in healthy tissue from an individual nothaving the disorder.

Thus, the invention provides a diagnostic method of a disorder, whichinvolves: (a) assaying gene expression level in cells or body fluid ofan individual; (b) comparing the gene expression level with a standardgene expression level, whereby an increase or decrease in the assayedgene expression level compared to the standard expression level isindicative of a disorder.

In the very least, the polynucleotides of the present invention can beused as molecular weight markers on Southern gels, as diagnostic probesfor the presence of a specific mRNA in a particular cell type, as aprobe to “subtract-out” known sequences in the process of discoveringnovel polynucleotides, for selecting and making oligomers for attachmentto a “gene chip” or other support, to raise anti-DNA antibodies usingDNA immunization techniques, and as an antigen to elicit an immuneresponse.

Uses of the Polypeptides

Each of the polypeptides identified herein can be used in numerous ways.The following description should be considered exemplary and utilizesknown techniques.

Polypeptides and antibodies directed to polypeptides of the presentinvention are useful to provide immunological probes for differentialidentification of the tissue(s) (e.g., immunohistochemistry assays suchas, for example, ABC immunoperoxidase (Hsu et al., J. Histochem.Cytochem. 29:577-580 (1981)) or cell type(s) (e.g., immunocytochemistryassays).

Antibodies can be used to assay levels of polypeptides encoded bypolynucleotides of the invention in a biological sample using classicalimmunohistological methods known to those of skill in the art (e.g., seeJalkanen, et al., J. Cell. Biol. 101:976-985 (1985); Jalkanen, et al.,J. Cell. Biol. 105:3087-3096 (1987)). Other antibody-based methodsuseful for detecting protein gene expression include immunoassays, suchas the enzyme linked immunosorbent assay (ELISA) and theradioimmunoassay (RIA). Suitable antibody assay labels are known in theart and include enzyme labels, such as, glucose oxidase; radioisotopes,such as iodine (¹³¹I, ¹²⁵I, ¹²³I, ¹²¹I), carbon (¹⁴C), sulfur (³⁵S),tritium (³H), indium (^(115m)In, ^(113m)In, ¹¹²In, ¹¹¹In), andtechnetium (⁹⁹Tc, ^(99m)Tc), thallium (²⁰¹Ti), gallium (⁶⁸Ga, ⁶⁷Ga),palladium (¹⁰³Pd), molybdenum (⁹⁹Mo), xenon (¹³³Xe), fluorine (¹⁸F),¹⁵³Sm, ¹⁷⁷Lu, ¹⁵⁹Gd, ¹⁴⁹Pm, ¹⁴⁰La, ¹⁷⁵Yb, ¹⁶⁶Ho, ⁹⁰Y, ⁴⁷Sc, ¹⁸⁶Re,¹⁸⁸Re, ¹⁴²Pr, ¹⁰⁵Rh, ⁹⁷Ru; luminescent labels, such as luminol; andfluorescent labels, such as fluorescein and rhodamine, and biotin.

In addition to assaying levels of polypeptide of the present inventionin a biological sample, proteins can also be detected in vivo byimaging. Antibody labels or markers for in vivo imaging of proteininclude those detectable by X-radiography, NMR or ESR. ForX-radiography, suitable labels include radioisotopes such as barium orcesium, which emit detectable radiation but are not overtly harmful tothe subject. Suitable markers for NMR and ESR include those with adetectable characteristic spin, such as deuterium, which may beincorporated into the antibody by labeling of nutrients for the relevanthybridoma.

A protein-specific antibody or antibody fragment which has been labeledwith an appropriate detectable imaging moiety, such as a radioisotope(for example, ¹³¹I, ¹¹²In, ^(99m)Tc, (¹³¹I, ¹²⁵I, ¹²³I, ¹²¹I), carbon(¹⁴C), sulfur (³⁵S), tritium (³H), indium (^(115m)In, ^(113m)In, ¹¹²In,¹¹¹In), and technetium (⁹⁹Tc, ⁹⁹Tc), thallium (²⁰¹Ti), gallium (⁶⁸Ga,⁶⁷Ga), palladium (¹⁰³Pd), molybdenum (⁹⁹Mo) xenon (¹³³Xe), fluorine(¹⁸F, ¹⁵³Sm, ¹⁷⁷Lu, ¹⁵⁹Gd, 149 Pm, ¹⁴⁰La, ¹⁷⁵Yb, ¹⁶⁶Ho, ⁹⁰Y, ⁴⁷Sc,¹⁸⁶Re, ¹⁸⁸Re, ¹⁴²Pr, ¹⁰⁵Rh, ⁹⁷Ru), a radio-opaque substance, or amaterial detectable by nuclear magnetic resonance, is introduced (forexample, parenterally, subcutaneously or intraperitoneally) into themammal to be examined for immune system disorder. It will be understoodin the art that the size of the subject and the imaging system used willdetermine the quantity of imaging moiety needed to produce diagnosticimages. In the case of a radioisotope moiety, for a human subject, thequantity of radioactivity injected will normally range from about 5 to20 millicuries of ^(99m)Tc. The labeled antibody or antibody fragmentwill then preferentially accumulate at the location of cells whichexpress the polypeptide encoded by a polynucleotide of the invention. Invivo tumor imaging is described in S. W. Burchiel et al.,“Immunopharmacokinetics of Radiolabeled Antibodies and Their Fragments”(Chapter 13 in Tumor Imaging: The Radiochemical Detection of Cancer, S.W. Burchiel and B. A. Rhodes, eds., Masson Publishing Inc. (1982)).

In one embodiment, the invention provides a method for the specificdelivery of compositions of the invention to cells by administeringpolypeptides of the invention (e.g., polypeptides encoded bypolynucleotides of the invention and/or antibodies) that are associatedwith heterologous polypeptides or nucleic acids. In one example, theinvention provides a method for delivering a therapeutic protein intothe targeted cell. In another example, the invention provides a methodfor delivering a single stranded nucleic acid (e.g., antisense orribozymes) or double stranded nucleic acid (e.g., DNA that can integrateinto the cell's genome or replicate episomally and that can betranscribed) into the targeted cell.

In another embodiment, the invention provides a method for the specificdestruction of cells (e.g., the destruction of tumor cells) byadministering polypeptides of the invention in association with toxinsor cytotoxic prodrugs.

By “toxin” is meant one or more compounds that bind and activateendogenous cytotoxic effector systems, radioisotopes, holotoxins,modified toxins, catalytic subunits of toxins, or any molecules orenzymes not normally present in or on the surface of a cell that underdefined conditions cause the cell's death. Toxins that may be usedaccording to the methods of the invention include, but are not limitedto, radioisotopes known in the art, compounds such as, for example,antibodies (or complement fixing containing portions thereof) that bindan inherent or induced endogenous cytotoxic effector system, thymidinekinase, endonuclease, RNAse, alpha toxin, ricin, abrin,Pseudomonasexotoxin A, diphtheria toxin, saporin, momordin, gelonin,pokeweed antiviral protein, alpha-sarcin and cholera toxin. “Toxin” alsoincludes a cytostatic or cytocidal agent, a therapeutic agent or aradioactive metal ion, e.g., alpha-emitters such as, for example, ²¹³Bi,or other radioisotopes such as, for example, ¹⁰³Pd, ¹³³Xe, ¹³¹I, ⁶⁸Ge,⁵⁷Co, ⁶⁵Zn, ⁸⁵Sr, ³²P, ³⁵S, ⁹⁰Y, ¹⁵³Sm, ¹⁵³Gd, ¹⁶⁹Yb, ⁵¹Cr, ⁵⁴Mn, ⁷⁵Se,¹¹³Sn, ⁹⁰Yttrium, ¹¹⁷Tin, ¹⁸⁶Rhenium, ¹⁶⁶Holmium, and ⁸⁸Rhenium;luminescent labels, such as luminol; and fluorescent labels, such asfluorescein and rhodamine, and biotin. In a specific embodiment, theinvention provides a method for the specific destruction of cells (e.g.,the destruction of tumor cells) by administering polypeptides of theinvention or antibodies of the invention in association with theradioisotope ⁹⁰Y. In another specific embodiment, the invention providesa method for the specific destruction of cells (e.g., the destruction oftumor cells) by administering polypeptides of the invention orantibodies of the invention in association with the radioisotope ¹¹¹In.In a further specific embodiment, the invention provides a method forthe specific destruction of cells (e.g., the destruction of tumor cells)by administering polypeptides of the invention or antibodies of theinvention in association with the radioisotope ¹³¹I.

Techniques known in the art may be applied to label polypeptides of theinvention (including antibodies). Such techniques include, but are notlimited to, the use of bifunctional conjugating agents (see e.g., U.S.Pat. Nos. 5,756,065; 5,714,631; 5,696,239; 5,652,361; 5,505,931;5,489,425; 5,435,990; 5,428,139; 5,342,604; 5,274,119; 4,994,560; and5,808,003; the contents of each of which are hereby incorporated byreference in its entirety).

Thus, the invention provides a diagnostic method of a disorder, whichinvolves (a) assaying the expression level of a polypeptide of thepresent invention in cells or body fluid of an individual; and (b)comparing the assayed polypeptide expression level with a standardpolypeptide expression level, whereby an increase or decrease in theassayed polypeptide expression level compared to the standard expressionlevel is indicative of a disorder. With respect to cancer, the presenceof a relatively high amount of transcript in biopsied tissue from anindividual may indicate a predisposition for the development of thedisease, or may provide a means for detecting the disease prior to theappearance of actual clinical symptoms. A more definitive diagnosis ofthis type may allow health professionals to employ preventative measuresor aggressive treatment earlier thereby preventing the development orfurther progression of the cancer.

Moreover, polypeptides of the present invention can be used to treat orprevent diseases or conditions such as, for example, neural disorders,immune system disorders, muscular disorders, reproductive disorders,gastrointestinal disorders, pulmonary disorders, cardiovasculardisorders, renal disorders, proliferative disorders, and/or cancerousdiseases and conditions. For example, patients can be administered apolypeptide of the present invention in an effort to replace absent ordecreased levels of the polypeptide (e.g., insulin), to supplementabsent or decreased levels of a different polypeptide (e.g., hemoglobinS for hemoglobin B, SOD, catalase, DNA repair proteins), to inhibit theactivity of a polypeptide (e.g., an oncogene or tumor supressor), toactivate the activity of a polypeptide (e.g., by binding to a receptor),to reduce the activity of a membrane bound receptor by competing with itfor free ligand (e.g., soluble TNF receptors used in reducinginflammation), or to bring about a desired response (e.g., blood vesselgrowth inhibition, enhancement of the immune response to proliferativecells or tissues).

Similarly, antibodies directed to a polypeptide of the present inventioncan also be used to treat disease (as described supra, and elsewhereherein). For example, administration of an antibody directed to apolypeptide of the present invention can bind, and/or neutralize thepolypeptide, and/or reduce overproduction of the polypeptide. Similarly,administration of an antibody can activate the polypeptide, such as bybinding to a polypeptide bound to a membrane (receptor).

At the very least, the polypeptides of the present invention can be usedas molecular weight markers on SDS-PAGE gels or on molecular sieve gelfiltration columns using methods well known to those of skill in theart. Polypeptides can also be used to raise antibodies, which in turnare used to measure protein expression from a recombinant cell, as a wayof assessing transformation of the host cell. Moreover, the polypeptidesof the present invention can be used to test the biological activitiesdescribed herein.

Diagnostic Assays

The compounds of the present invention are useful for diagnosis,treatment, prevention and/or prognosis of various disorders in mammals,preferably humans. Such disorders include, but are not limited to, thoserelated to biological activities described in Table 1D and, also asdescribed herein under the section heading “Biological Activities”.

For a number of disorders, substantially altered (increased ordecreased) levels of gene expression can be detected in tissues, cellsor bodily fluids (e.g., sera, plasma, urine, semen, synovial fluid orspinal fluid) taken from an individual having such a disorder, relativeto a “standard” gene expression level, that is, the expression level intissues or bodily fluids from an individual not having the disorder.Thus, the invention provides a diagnostic method useful during diagnosisof a disorder, which involves measuring the expression level of the geneencoding the polypeptide in tissues, cells or body fluid from anindividual and comparing the measured gene expression level with astandard gene expression level, whereby an increase or decrease in thegene expression level(s) compared to the standard is indicative of adisorder. These diagnostic assays may be performed in vivo or in vitro,such as, for example, on blood samples, biopsy tissue or autopsy tissue.

The present invention is also useful as a prognostic indicator, wherebypatients exhibiting enhanced or depressed gene expression willexperience a worse clinical outcome relative to patients expressing thegene at a level nearer the standard level.

In certain embodiments, a polypeptide of the invention, orpolynucleotides, antibodies, agonists, or antagonists corresponding tothat polypeptide, may be used to diagnose and/or prognosticate diseasesand/or disorders associated with the tissue(s) in which the polypeptideof the invention is expressed, including one, two, three, four, five, ormore tissues disclosed in Table 1B.2 (Tissue Distribution Library Code).

By “assaying the expression level of the gene encoding the polypeptide”is intended qualitatively or quantitatively measuring or estimating thelevel of the polypeptide of the invention or the level of the mRNAencoding the polypeptide of the invention in a first biological sampleeither directly (e.g., by determining or estimating absolute proteinlevel or mRNA level) or relatively (e.g., by comparing to thepolypeptide level or mRNA level in a second biological sample).Preferably, the polypeptide expression level or mRNA level in the firstbiological sample is measured or estimated and compared to a standardpolypeptide level or mRNA level, the standard being taken from a secondbiological sample obtained from an individual not having the disorder orbeing determined by averaging levels from a population of individualsnot having the disorder. As will be appreciated in the art, once astandard polypeptide level or mRNA level is known, it can be usedrepeatedly as a standard for comparison.

By “biological sample” is intended any biological sample obtained froman individual, cell line, tissue culture, or other source containingpolypeptides of the invention (including portions thereof) or mRNA. Asindicated, biological samples include body fluids (such as sera, plasma,urine, synovial fluid and spinal fluid) and tissue sources found toexpress the full length or fragments thereof of a polypeptide or mRNA.Methods for obtaining tissue biopsies and body fluids from mamas arewell known in the art. Where the biological sample is to include mRNA, atissue biopsy is the preferred source.

Total cellular RNA can be isolated from a biological sample using anysuitable technique such as the single-stepguanidinium-thiocyanate-phenol-chloroform method described inChomczynski and Sacchi, Anal. Biochem. 162:156-159 (1987). Levels ofmRNA encoding the polypeptides of the invention are then assayed usingany appropriate method. These include Northern blot analysis, S1nuclease mapping, the polymerase chain reaction (PCR), reversetranscription in combination with the polymerase chain reaction(RT-PCR), and reverse transcription in combination with the ligase chainreaction (RT-LCR).

The present invention also relates to diagnostic assays such asquantitative and diagnostic assays for detecting levels of polypeptidesof the invention, in a biological sample (e.g., cells and tissues),including determination of normal and abnormal levels of polypeptides.Thus, for instance, a diagnostic assay in accordance with the inventionfor detecting over-expression of polypeptides of the invention comparedto normal control tissue samples may be used to detect the presence oftumors. Assay techniques that can be used to determine levels of apolypeptide, such as a polypeptide of the present invention in a samplederived from a host are well-known to those of skill in the art. Suchassay methods include radioimmunoassays, competitive-binding assays,Western Blot analysis and ELISA assays. Assaying polypeptide levels in abiological sample can occur using any art-known method.

Assaying polypeptide levels in a biological sample can occur usingantibody-based techniques. For example, polypeptide expression intissues can be studied with classical immunohistological methods(Jalkanen et al., J. Cell. Biol. 101:976-985 (1985); Jalkanen, M., etal., J. Cell. Biol. 105:3087-3096 (1987)). Other antibody-based methodsuseful for detecting polypeptide gene expression include immunoassays,such as the enzyme linked immunosorbent assay (ELISA) and theradioimmunoassay (RIA). Suitable antibody assay labels are known in theart and include enzyme labels, such as, glucose oxidase, andradioisotopes, such as iodine (¹²⁵I, ¹²¹I, carbon (¹⁴C), sulfur (³⁵S),tritium (³H), indium (¹¹²In), and technetium (^(99m)Tc), and fluorescentlabels, such as fluorescein and rhodamine, and biotin.

The tissue or cell type to be analyzed will generally include thosewhich are known, or suspected, to express the gene of interest (such as,for example, cancer). The protein isolation methods employed herein may,for example, be such as those described in Harlow and Lane (Harlow, E.and Lane, D., 1988, “Antibodies: A Laboratory Manual”, Cold SpringHarbor Laboratory Press, Cold Spring Harbor, N.Y.), which isincorporated herein by reference in its entirety. The isolated cells canbe derived from cell culture or from a patient. The analysis of cellstaken from culture may be a necessary step in the assessment of cellsthat could be used as part of a cell-based gene therapy technique or,alternatively, to test the effect of compounds on the expression of thegene.

For example, antibodies, or fragments of antibodies, such as thosedescribed herein, may be used to quantitatively or qualitatively detectthe presence of gene products or conserved variants or peptide fragmentsthereof. This can be accomplished, for example, by immunofluorescencetechniques employing a fluorescently labeled antibody coupled with lightmicroscopic, flow cytometric, or fluorimetric detection.

In a preferred embodiment, antibodies, or fragments of antibodiesdirected to any one or all of the predicted epitope domains of thepolypeptides of the invention (shown in Table 1B) may be used toquantitatively or qualitatively detect the presence of gene products orconserved variants or peptide fragments thereof. This can beaccomplished, for example, by immunofluorescence techniques employing afluorescently labeled antibody coupled with light microscopic, flowcytometric, or fluorimetric detection.

In an additional preferred embodiment, antibodies, or fragments ofantibodies directed to a conformational epitope of a polypeptide of theinvention may be used to quantitatively or qualitatively detect thepresence of gene products or conserved variants or peptide fragmentsthereof. This can be accomplished, for example, by immunofluorescencetechniques employing a fluorescently labeled antibody coupled with lightmicroscopic, flow cytometric, or fluorimetric detection.

The antibodies (or fragments thereof), and/or polypeptides of thepresent invention may, additionally, be employed histologically, as inimmunofluorescence, immunoelectron microscopy or non-immunologicalassays, for in situ detection of gene products or conserved variants orpeptide fragments thereof. In situ detection may be accomplished byremoving a histological specimen from a patient, and applying thereto alabeled antibody or polypeptide of the present invention. The antibody(or fragment thereof) or polypeptide is preferably applied by overlayingthe labeled antibody (or fragment) onto a biological sample. Through theuse of such a procedure, it is possible to determine not only thepresence of the gene product, or conserved variants or peptidefragments, or polypeptide binding, but also its distribution in theexamined tissue. Using the present invention, those of ordinary skillwill readily perceive that any of a wide variety of histological methods(such as staining procedures) can be modified in order to achieve suchin situ detection.

Immunoassays and non-immunoassays for gene products or conservedvariants or peptide fragments thereof will typically comprise incubatinga sample, such as a biological fluid, a tissue extract, freshlyharvested cells, or lysates of cells which have been incubated in cellculture, in the presence of a detectably labeled antibody capable ofbinding gene products or conserved variants or peptide fragmentsthereof, and detecting the bound antibody by any of a number oftechniques well-known in the art.

The biological sample may be brought in contact with and immobilizedonto a solid phase support or carrier such as nitrocellulose, or othersolid support which is capable of immobilizing cells, cell particles orsoluble proteins. The support may then be washed with suitable buffersfollowed by treatment with the detectably labeled antibody or detectablepolypeptide of the invention. The solid phase support may then be washedwith the buffer a second time to remove unbound antibody or polypeptide.Optionally the antibody is subsequently labeled. The amount of boundlabel on solid support may then be detected by conventional means.

By “solid phase support or carrier” is intended any support capable ofbinding an antigen or an antibody. Well-known supports or carriersinclude glass, polystyrene, polypropylene, polyethylene, dextran, nylon,amylases, natural and modified celluloses, polyacrylamides, gabbros, andmagnetite. The nature of the carrier can be either soluble to someextent or insoluble for the purposes of the present invention. Thesupport material may have virtually any possible structuralconfiguration so long as the coupled molecule is capable of binding toan antigen or antibody. Thus, the support configuration may bespherical, as in a bead, or cylindrical, as in the inside surface of atest tube, or the external surface of a rod. Alternatively, the surfacemay be flat such as a sheet, test strip, etc. Preferred supports includepolystyrene beads. Those skilled in the art will know many othersuitable carriers for binding antibody or antigen, or will be able toascertain the same by use of routine experimentation.

The binding activity of a given lot of antibody or antigen polypeptidemay be determined according to well known methods. Those skilled in theart will be able to determine operative and optimal assay conditions foreach determination by employing routine experimentation.

In addition to assaying polypeptide levels or polynucleotide levels in abiological sample obtained from an individual, polypeptide orpolynucleotide can also be detected in vivo by imaging. For example, inone embodiment of the invention, polypeptides and/or antibodies of theinvention are used to image diseased cells, such as neoplasms. Inanother embodiment, polynucleotides of the invention (e.g.,polynucleotides complementary to all or a portion of an mRNA) and/orantibodies (e.g., antibodies directed to any one or a combination of theepitopes of a polypeptide of the invention, antibodies directed to aconformational epitope of a polypeptide of the invention, or antibodiesdirected to the full length polypeptide expressed on the cell surface ofa mammalian cell) are used to image diseased or neoplastic cells.

Antibody labels or markers for in vivo imaging of polypeptides of theinvention include those detectable by X-radiography, NMR, MRI, CAT-scansor ESR. For X-radiography, suitable labels include radioisotopes such asbarium or cesium, which emit detectable radiation but are not overtlyharmful to the subject. Suitable markers for NMR and ESR include thosewith a detectable characteristic spin, such as deuterium, which may beincorporated into the antibody by labeling of nutrients for the relevanthybridoma. Where in vivo imaging is used to detect enhanced levels ofpolypeptides for diagnosis in humans, it may be preferable to use humanantibodies or “humanized” chimeric monoclonal antibodies. Suchantibodies can be produced using techniques described herein orotherwise known in the art. For example methods for producing chimericantibodies are known in the art. See, for review, Morrison, Science229:1202 (1985); Oi et al., BioTechniques 4:214 (1986); Cabilly et al.,U.S. Pat. No. 4,816,567; Taniguchi et al., EP 171496; Morrison et al.,EP 173494; Neuberger et al., WO 8601533; Robinson et al., WO 8702671;Boulianne et al., Nature 312:643 (1984); Neuberger et al., Nature314:268 (1985).

Additionally, any polypeptides of the invention whose presence can bedetected, can be administered. For example, polypeptides of theinvention labeled with a radio-opaque or other appropriate compound canbe administered and visualized in vivo, as discussed, above for labeledantibodies. Further, such polypeptides can be utilized for in vitrodiagnostic procedures.

A polypeptide-specific antibody or antibody fragment which has beenlabeled with an appropriate detectable imaging moiety, such as aradioisotope (for example, ¹³¹I, ¹¹²In, ^(99m)Tc), a radio-opaquesubstance, or a material detectable by nuclear magnetic resonance, isintroduced (for example, parenterally, subcutaneously orintraperitoneally) into the mammal to be examined for a disorder. Itwill be understood in the art that the size of the subject and theimaging system used will determine the quantity of imaging moiety neededto produce diagnostic images. In the case of a radioisotope moiety, fora human subject, the quantity of radioactivity injected will normallyrange from about 5 to 20 millicuries of ^(99m)Tc. The labeled antibodyor antibody fragment will then preferentially accumulate at the locationof cells which contain the antigenic protein. In vivo tumor imaging isdescribed in S. W. Burchiel et al., “Immunopharmacokinetics ofRadiolabeled Antibodies and Their Fragments” (Chapter 13 in TumorImaging: The Radiochemical Detection of Cancer, S. W. Burchiel and B. A.Rhodes, eds., Masson Publishing Inc. (1982)).

With respect to antibodies, one of the ways in which an antibody of thepresent invention can be detectably labeled is by linking the same to areporter enzyme and using the linked product in an enzyme immunoassay(EIA) (Voller, A., “The Enzyme Linked Immunosorbent Assay (ELISA)”,1978, Diagnostic Horizons 2:1-7, Microbiological Associates QuarterlyPublication, Walkersville, Md.); Voller et al., J. Clin. Pathol.31:507-520 (1978); Butler, J. E., Meth Enzymol. 73:482-523 (1981);Maggio, E. (ed.), 1980, Enzyme Immunoassay, CRC Press, Boca Raton,Fla.,; Ishikawa, E. et al., (eds.), 1981, Enzyme Immunoassay, KgakuShoin, Tokyo). The reporter enzyme which is bound to the antibody willreact with an appropriate substrate, preferably a chromogenic substrate,in such a manner as to produce a chemical moiety which can be detected,for example, by spectrophotometric, fluorimetric or by visual means.Reporter enzymes which can be used to detectably label the antibodyinclude, but are not limited to, malate dehydrogenase, staphylococcalnuclease, delta-5-steroid isomerase, yeast alcohol dehydrogenase,alpha-glycerophosphate, dehydrogenase, triose phosphate isomerase,horseradish peroxidase, alkaline phosphatase, asparaginase, glucoseoxidase, beta-galactosidase, ribonuclease, urease, catalase,glucose-6-phosphate dehydrogenase, glucoamylase andacetylcholinesterase. Additionally, the detection can be accomplished bycolorimetric methods which employ a chromogenic substrate for thereporter enzyme. Detection may also be accomplished by visual comparisonof the extent of enzymatic reaction of a substrate in comparison withsimilarly prepared standards.

Detection may also be accomplished using any of a variety of otherimmunoassays. For example, by radioactively labeling the antibodies orantibody fragments, it is possible to detect polypeptides through theuse of a radioimmunoassay (RIA) (see, for example, Weintraub, B.,Principles of Radioimmunoassays, Seventh Training Course on RadioligandAssay Techniques, The Endocrine Society, March, 1986, which isincorporated by reference herein). The radioactive isotope can bedetected by means including, but not limited to, a gamma counter, ascintillation counter, or autoradiography.

It is also possible to label the antibody with a fluorescent compound.When the fluorescently labeled antibody is exposed to light of theproper wave length, its presence can then be detected due tofluorescence. Among the most commonly used fluorescent labelingcompounds are fluorescein isothiocyanate, rhodamine, phycoerythrin,phycocyanin, allophycocyanin, ophthaldehyde and fluorescamine.

The antibody can also be detectably labeled using fluorescence emittingmetals such as ¹⁵²Eu, or others of the lanthanide series. These metalscan be attached to the antibody using such metal chelating groups asdiethylenetriaminepentacetic acid (DTPA) or ethylenediaminetetraaceticacid (EDTA).

The antibody also can be detectably labeled by coupling it to achemiluminescent compound. The presence of the chemiluminescent-taggedantibody is then determined by detecting the presence of luminescencethat arises during the course of a chemical reaction. Examples ofparticularly useful chemiluminescent labeling compounds are luminol,isoluminol, theromatic acridinium ester, imidazole, acridinium salt andoxalate ester.

Likewise, a bioluminescent compound may be used to label the antibody ofthe present invention. Bioluminescence is a type of chemiluminescencefound in biological systems in, which a catalytic protein increases theefficiency of the chemiluminescent reaction. The presence of abioluminescent protein is determined by detecting the presence ofluminescence. Important bioluminescent compounds for purposes oflabeling are luciferin, luciferase and aequorin.

Methods for Detecting Diseases

In general, a disease may be detected in a patient based on the presenceof one or more proteins of the invention and/or polynucleotides encodingsuch proteins in a biological sample (for example, blood, sera, urine,and/or tumor biopsies) obtained from the patient. In other words, suchproteins may be used as markers to indicate the presence or absence of adisease or disorder, including cancer and/or as described elsewhereherein. In addition, such proteins may be useful for the detection ofother diseases and cancers. The binding agents provided herein generallypermit detection of the level of antigen that binds to the agent in thebiological sample. Polynucleotide primers and probes may be used todetect the level of mRNA encoding polypeptides of the invention, whichis also indicative of the presence or absence of a disease or disorder,including cancer. In general, polypeptides of the invention should bepresent at a level that is at least three fold higher in diseased tissuethan in normal tissue.

There are a variety of assay formats known to those of ordinary skill inthe art for using a binding agent to detect polypeptide markers in asample. See, e.g., Harlow and Lane, supra. In general, the presence orabsence of a disease in a patient may be determined by (a) contacting abiological sample obtained from a patient with a binding agent; (b)detecting in the sample a level of polypeptide that binds to the bindingagent; and (c) comparing the level of polypeptide with a predeterminedcut-off value.

In a preferred embodiment, the assay involves the use of a bindingagent(s) immobilized on a solid support to bind to and remove thepolypeptide of the invention from the remainder of the sample. The boundpolypeptide may then be detected using a detection reagent that containsa reporter group and specifically binds to the binding agent/polypeptidecomplex. Such detection reagents may comprise, for example, a bindingagent that specifically binds to the polypeptide or an antibody or otheragent that specifically binds to the binding agent, such as ananti-immunoglobulin, protein G, protein A or a lectin. Alternatively, acompetitive assay may be utilized, in which a polypeptide is labeledwith a reporter group and allowed to bind to the immobilized bindingagent after incubation of the binding agent with the sample. The extentto which components of the sample inhibit the binding of the labeledpolypeptide to the binding agent is indicative of the reactivity of thesample with the immobilized binding agent. Suitable polypeptides for usewithin such assays include polypeptides of the invention and portionsthereof, or antibodies, to which the binding agent binds, as describedabove.

The solid support may be any material known to those of skill in the artto which polypeptides of the invention may be attached. For example, thesolid support may be a test well in a microtiter plate or anitrocellulose or other suitable membrane. Alternatively, the supportmay be a bead or disc, such as glass fiberglass, latex or a plasticmaterial such as polystyrene or polyvinylchloride. The support may alsobe a magnetic particle or a fiber optic sensor, such as those disclosed,for example, in U.S. Pat. No. 5,359,681. The binding agent may beimmobilized on the solid support using a variety of techniques known tothose of skill in the art, which are amply described in the patent andscientific literature. In the context of the present invention, the term“immobilization” refers to both noncovalent association, such asadsorption, and covalent attachment (which may be a direct linkagebetween the agent and functional groups on the support or may be alinkage by way of a cross-linking agent). Immobilization by adsorptionto a well in a microtiter plate or to a membrane is preferred. In suchcases, adsorption may be achieved by contacting the binding agent, in asuitable buffer, with the solid support for the suitable amount of tine.The contact time varies with temperature, but is typically between about1 hour and about 1 day. In general, contacting a well of plasticmicrotiter plate (such as polystyrene or polyvinylchloride) with anamount of binding agent ranging from about 10 ng to about 10 ug, andpreferably about 100 ng to about 1 ug, is sufficient to immobilize anadequate amount of binding agent.

Covalent attachment of binding agent to a solid support may generally beachieved by first reacting the support with a bifunctional reagent thatwill react with both the support and a functional group, such as ahydroxyl or amino group, on the binding agent. For example, the bindingagent may be covalently attached to supports having an appropriatepolymer coating using benzoquinone or by condensation of an aldehydegroup on the support with an amine and an active hydrogen on the bindingpartner (see, e.g., Pierce Immunotechnology Catalog and Handbook, 1991,at A12-A13).

Gene Therapy Methods

Also encompassed by the invention are gene therapy methods for treatingor preventing disorders, diseases and conditions. The gene therapymethods relate to the introduction of nucleic acid (DNA, RNA andantisense DNA or RNA) sequences into an animal to achieve expression ofthe polypeptide of the present invention. This method requires apolynucleotide which codes for a polypeptide of the present inventionoperatively linked to a promoter and any other genetic elementsnecessary for the expression of the polypeptide by the target tissue.Such gene therapy and delivery techniques are known in the art, see, forexample, WO90/11092, which is herein incorporated by reference.

Thus, for example, cells from a patient may be engineered with apolynucleotide (DNA or RNA) comprising a promoter operably linked to apolynucleotide of the present invention ex vivo, with the engineeredcells then being provided to a patient to be treated with thepolypeptide of the present invention. Such methods are well-known in theart. For example, see Belldegrun, A., et al., J. Natl. Cancer Inst. 85:207-216 (1993); Ferrantini, M. et al., Cancer Research 53: 1107-1112(1993); Ferrantini, M. et al., J. Immunology 153: 4604-4615 (1994);Kaido, T., et al., Int. J. Cancer 60: 221-229 (1995); Ogura, H., et al.,Cancer Research 50: 5102-5106 (1990); Santodonato, L., et al., HumanGene Therapy 7:1-10 (1996); Santodonato, L., et al., Gene Therapy4:1246-1255 (1997); and Zhang, J.-F. et al., Cancer Gene Therapy 3:31-38 (1996)), which are herein incorporated by reference. In oneembodiment, the cells which are engineered are arterial cells. Thearterial cells may be reintroduced into the patient through directinjection to the artery, the tissues surrounding the artery, or throughcatheter injection.

As discussed in more detail below, the polynucleotide constructs can bedelivered by any method that delivers injectable materials to the cellsof an animal, such as, injection into the interstitial space of tissues(heart, muscle, skin, lung, liver, and the like). The polynucleotideconstructs may be delivered in a pharmaceutically acceptable liquid oraqueous carrier.

In one embodiment, the polynucleotide of the present invention isdelivered as a naked polynucleotide. The term “naked” polynucleotide,DNA or RNA refers to sequences that are free from any delivery vehiclethat acts to assist, promote or facilitate entry into the cell,including viral sequences, viral particles, liposome formulations,lipofectin or precipitating agents and the like. However, thepolynucleotide of the present invention can also be delivered inliposome formulations and lipofectin formulations and the like can beprepared by methods well known to those skilled in the art. Such methodsare described, for example, in U.S. Pat. Nos. 5,593,972, 5,589,466, and5,580,859, which are herein incorporated by reference.

The polynucleotide vector constructs used in the gene therapy method arepreferably constructs that will not integrate into the host genome norwill they contain sequences that allow for replication. Appropriatevectors include p 0, pSV2CAT, pOG44, pXT1 and pSG available fromStratagene; pSVK3, pBPV, pMSG and pSVL available from Pharmacia; andpEF1/V5, pcDNA3.1, and pRc/CMV2 available from Invitrogen. Othersuitable vectors will be readily apparent to the skilled artisan.

Any strong promoter known to those skilled in the art can be used fordriving the expression of the polynucleotide sequence. Suitablepromoters include adenoviral promoters, such as the adenoviral majorlate promoter; or heterologous promoters, such as the cytomegalovirus(CMV) promoter; the respiratory syncytial virus (RSV) promoter;inducible promoters, such as the MMT promoter, the metallothioneinpromoter; heat shock promoters; the albumin promoter; the ApoAIpromoter; human globin promoters; viral thymidine kinase promoters, suchas the Herpes Simplex thymidine kinase promoter; retroviral LTRs; theb-actin promoter; and human growth hormone promoters. The promoter alsomay be the native promoter for the polynucleotide of the presentinvention.

Unlike other gene therapy techniques, one major advantage of introducingnaked nucleic acid sequences into target cells is the transitory natureof the polynucleotide synthesis in the cells. Studies have shown thatnon-replicating DNA sequences can be introduced into cells to provideproduction of the desired polypeptide for periods of up to six months.

The polynucleotide construct can be delivered to the interstitial spaceof tissues within the an animal, including of muscle, skin, brain, lung,liver, spleen, bone marrow, thymus, heart, lymph, blood, bone,cartilage, pancreas, kidney, gall bladder, stomach, intestine, testis,ovary, uterus, rectum, nervous system, eye, gland, and connectivetissue. Interstitial space of the tissues comprises the intercellular,fluid, mucopolysaccharide matrix among the reticular fibers of organtissues, elastic fibers in the walls of vessels or chambers, collagenfibers of fibrous tissues, or that same matrix within connective tissueensheathing muscle cells or in the lacunae of bone. It is similarly thespace occupied by the plasma of the circulation and the lymph fluid ofthe lymphatic channels. Delivery to the interstitial space of muscletissue is preferred for the reasons discussed below. They may beconveniently delivered by injection into the tissues comprising thesecells. They are preferably delivered to and expressed in persistent,non-dividing cells which are differentiated, although delivery andexpression may be achieved in non-differentiated or less completelydifferentiated cells, such as, for example, stem cells of blood or skinfibroblasts. In vivo muscle cells are particularly competent in theirability to take up and express polynucleotides.

For the naked nucleic acid sequence injection, an effective dosageamount of DNA or RNA will be in the range of from about 0.05 mg/kg bodyweight to about 50 mg/kg body weight. Preferably the dosage will be fromabout 0.005 mg/kg to about 20 mg/kg and more preferably from about 0.05mg/kg to about 5 mg/kg. Of course, as the artisan of ordinary skill willappreciate, this dosage will vary according to the tissue site ofinjection. The appropriate and effective dosage of nucleic acid sequencecan readily be determined by those of ordinary skill in the art and maydepend on the condition being treated and the route of administration.

The preferred route of administration is by the parenteral route ofinjection into the interstitial space of tissues. However, otherparenteral routes may also be used, such as, inhalation of an aerosolformulation particularly for delivery to lungs or bronchial tissues,throat or mucous membranes of the nose. In addition, naked DNAconstructs can be delivered to arteries during angioplasty by thecatheter used in the procedure.

The naked polynucleotides are delivered by any method known in the art,including, but not limited to, direct needle injection at the deliverysite, intravenous injection, topical administration, catheter infusion,and so-called “gene guns”. These delivery methods are known in the art.

The constructs may also be delivered with delivery vehicles such asviral sequences, viral particles, liposome formulations, lipofectin,precipitating agents, etc. Such methods of delivery are known in theart.

In certain embodiments, the polynucleotide constructs are complexed in aliposome preparation. Liposomal preparations for use in the instantinvention include cationic (positively charged), anionic (negativelycharged) and neutral preparations. However, cationic liposomes areparticularly preferred because a tight charge complex can be formedbetween the cationic liposome and the polyanionic nucleic acid. Cationicliposomes have been shown to mediate intracellular delivery of plasmidDNA (Felgner et al., Proc. Natl. Acad. Sci. USA (1987) 84:7413-7416,which is herein incorporated by reference); mRNA (Malone et al., Proc.Natl. Acad. Sci. USA (1989) 86:6077-6081, which is herein incorporatedby reference); and purified transcription factors (Debs et al., J. Biol.Chem. (1990) 265:10189-10192, which is herein incorporated byreference), in functional form.

Cationic liposomes are readily available. For example,N[1-2,3-dioleyloxy)propyl]-N,N,N-triethylammonium (DOTMA) liposomes areparticularly useful and are available under the trademark Lipofectin,from GIBCO BRL, Grand Island, N.Y. (See, also, Felgner et al., Proc.Natl. Acad. Sci. USA (1987) 84:7413-7416, which is herein incorporatedby reference). Other commercially available liposomes includetransfectace (DDAB/DOPE) and DOTAP/DOPE (Boehringer).

Other cationic liposomes can be prepared from readily availablematerials using techniques well known in the art. See, e.g. PCTPublication No. WO 90/11092 (which is herein incorporated by reference)for a description of the synthesis of DOTAP(1,2-bis(oleoyloxy)-3-(trirethylammonio)propane) liposomes. Preparationof DOTMA liposomes is explained in the literature, see, e.g., P. Felgneret al., Proc. Natl. Acad. Sci. USA 84:7413-7417, which is hereinincorporated by reference. Similar methods can be used to prepareliposomes from other cationic lipid materials.

Similarly, anionic and neutral liposomes are readily available, such asfrom Avanti Polar Lipids (Birmingham, Ala.), or can be easily preparedusing readily available materials. Such materials include phosphatidyl,choline, cholesterol, phosphatidyl ethanolamine, dioleoylphosphatidylcholine (DOPC), dioleoylphosphatidyl glycerol (DOPG),dioleoylphoshatidyl ethanolamine (DOPE), among others. These materialscan also be mixed with the DOTMA and DOTAP starting materials inappropriate ratios. Methods for making liposomes using these materialsare well known in the art.

For example, commercially dioleoylphosphatidyl choline (DOPC),dioleoylphosphatidyl glycerol (DOPG), and dioleoylphosphatidylethanolamine (DOPE) can be used in various combinations to makeconventional liposomes, with or without the addition of cholesterol.Thus, for example, DOPG/DOPC vesicles can be prepared by drying 50 mgeach of DOPG and DOPC under a stream of nitrogen gas into a sonicationvial. The sample is placed under a vacuum pump overnight and is hydratedthe following day with deionized water. The sample is then sonicated for2 hours in a capped vial, using a Heat Systems model 350 sonicatorequipped with an inverted cup (bath type) probe at the maximum settingwhile the bath is circulated at 15 EC. Alternatively, negatively chargedvesicles can be prepared without sonication to produce multilamellarvesicles or by extrusion through nucleopore membranes to produceunilamellar vesicles of discrete size. Other methods are known andavailable to those of skill in the art.

The liposomes can comprise multilamellar vesicles (MLVs), smallunilamellar vesicles (SUVs), or large unilamellar vesicles (LUVs), withSUVs being preferred. The various liposome-nucleic acid complexes areprepared using methods well known in the art. See, e.g., Straubinger etal., Methods of Immunology (1983), 101:512-527, which is hereinincorporated by reference. For example, MLVs containing nucleic acid canbe prepared by depositing a thin film of phospholipid on the walls of aglass tube and subsequently hydrating with a solution of the material tobe encapsulated. SUVs are prepared by extended sonication of MLVs toproduce a homogeneous population of unilamellar liposomes. The materialto be entrapped is added to a suspension of preformed MLVs and thensonicated. When using liposomes containing cationic lipids, the driedlipid film is resuspended in an appropriate solution such as sterilewater or an isotonic buffer solution such as 10 mM Tris/NaCl, sonicated,and then the preformed liposomes are mixed directly with the DNA. Theliposome and DNA form a very stable complex due to binding of thepositively charged liposomes to the cationic DNA. SUVs find use withsmall nucleic acid fragments. LUVs are prepared by a number of methods,well known in the art. Commonly used methods include Ca²⁺-EDTA chelation(Papahadjopoulos et al., Biochim Biophys. Acta (1975) 394:483; Wilson etal., Cell 17:77 (1979)); ether injection (Deamer, D. and Bangham, A.,Biochim. Biophys. Acta 443:629 (1976); Ostro et al., Biochem. Biophys.Res. Commun. 76:836 (1977); Fraley et al., Proc. Natl. Acad. Sci. USA76:3348 (1979)); detergent dialysis (Enoch, H. and Strittmatter, P.,Proc. Natl. Acad. Sci. USA 76:145 (1979)); and reverse-phase evaporation(REV) (Fraley et al., J. Biol. Chem. 255:10431 (1980); Szoka, F. andPapahadjopoulos, D., Proc. Natl. Acad. Sci. USA 75:145 (1978);Schaefer-Ridder et al., Science 215:166 (1982)), which are hereinincorporated by reference.

Generally, the ratio of DNA to liposomes will be from about 10:1 toabout 1:10. Preferably, the ration will be from about 5:1 to about 1:5.More preferably, the ration will be about 3:1 to about 1:3. Still morepreferably, the ratio will be about 1:1.

U.S. Pat. No. 5,676,954 (which is herein incorporated by reference)reports on the injection of genetic material, complexed with cationicliposomes carriers, into mice. U.S. Pat. Nos. 4,897,355, 4,946,787,5,049,386, 5,459,127, 5,589,466, 5,693,622, 5,580,859, 5,703,055, andinternational publication no. WO 94/9469 (which are herein incorporatedby reference) provide cationic lipids for use in transfecting DNA intocells and mammals. U.S. Pat. Nos. 5,589,466, 5,693,622, 5,580,859,5,703,055, and international publication no. WO 94/9469 provide methodsfor delivering DNA-cationic lipid complexes to mammals.

In certain embodiments, cells are engineered, ex vivo or in vivo, usinga retroviral particle containing RNA which comprises a sequence encodinga polypeptide of the present invention. Retroviruses from which theretroviral plasmid vectors may be derived include, but are not limitedto, Moloney Murine Leukemia Virus, spleen necrosis virus, Rous sarcomaVirus, Harvey Sarcoma Virus, avian leukosis virus, gibbon ape leukemiavirus, human immunodeficiency virus, Myeloproliferative Sarcoma Virus,and mammary tumor virus.

The retroviral plasmid vector is employed to transduce packaging celllines to form producer cell lines. Examples of packaging cells which maybe transfected include, but are not limited to, the PE501, PA317, R-2,R-AM, PA12, T19-14×, VT-19-17-H2, RCRE, RCRIP, GP+E-86, GP+envAm12, andDAN cell lines as described in Miller, Human Gene Therapy 1:5-14 (1990),which is incorporated herein by reference in its entirety. The vectormay transduce the packaging cells through any means known in the art.Such means include, but are not limited to, electroporation, the use ofliposomes, and CaPO₄ precipitation. In one alternative, the retroviralplasmid vector may be encapsulated into a liposome, or coupled to alipid, and then administered to a host.

The producer cell line generates infectious retroviral vector particleswhich include polynucleotide encoding a polypeptide of the presentinvention. Such retroviral vector particles then may be employed, totransduce eukaryotic cells, either in vitro or in vivo. The transducedeukaryotic cells will express a polypeptide of the present invention.

In certain other embodiments, cells are engineered, ex vivo or in vivo,with polynucleotide contained in an adenovirus vector. Adenovirus can bemanipulated such that it encodes and expresses a polypeptide of thepresent invention, and at the same time is inactivated in terms of itsability to replicate in a normal lytic viral life cycle. Adenovirusexpression is achieved without integration of the viral DNA into thehost cell chromosome, thereby alleviating concerns about insertionalmutagenesis. Furthermore, adenoviruses have been used as live entericvaccines for many years with an excellent safety profile (Schwartz etal. Am. Rev. Respir. Dis.109:233-238 (1974)). Finally, adenovirusmediated gene transfer has been demonstrated in a number of instancesincluding transfer of alpha-1-antitrypsin and CFTR to the lungs ofcotton rats (Rosenfeld, M. A. et al. (1991) Science 252:431-434;Rosenfeld et al., (1992) Cell 68:143-155). Furthermore, extensivestudies to attempt to establish adenovirus as a causative agent in humancancer were uniformly negative (Green, M. et al. (1979) Proc. Natl.Acad. Sci. USA 76:6606).

Suitable adenoviral vectors useful in the present invention aredescribed, for example, in Kozarsky and Wilson, Curr. Opin. Genet.Devel. 3:499-503 (1993); Rosenfeld et al., Cell 68:143-155 (1992);Engelhardt et al., Human Genet. Ther. 4:759-769 (1993); Yang et al.,Nature Genet. 7:362-369 (1994); Wilson et al., Nature 365:691-692(1993); and U.S. Pat. No. 5,652,224, which are herein incorporated byreference. For example, the adenovirus vector Ad2 is useful and can begrown in human 293 cells. These cells contain the E1 region ofadenovirus and constitutively express E1a and E1b, which complement thedefective adenoviruses by providing the products of the genes deletedfrom the vector. In addition to Ad2, other varieties of adenovirus(e.g., Ad3, Ad5, and Ad7) are also useful in the present invention.

Preferably, the adenoviruses used in the present invention arereplication deficient. Replication deficient adenoviruses require theaid of a helper virus and/or packaging cell line to form infectiousparticles. The resulting virus is capable of infecting cells and canexpress a polynucleotide of interest which is operably linked to apromoter, but cannot replicate in most cells. Replication deficientadenoviruses may be deleted in one or more of all or a portion of thefollowing genes: E1a, E1b, E3, E4, E2a, or L1 through L5.

In certain other embodiments, the cells are engineered, ex vivo or invivo, using an adeno-associated virus (AAV). AAVs are naturallyoccurring defective viruses that require helper viruses to produceinfectious particles (Muzyczka, N., Curr. Topics in Microbiol. Immunol.158:97 (1992)). It is also one of the few viruses that may integrate itsDNA into non-dividing cells. Vectors containing as little as 300 basepairs of AAV can be packaged and can integrate, but space for exogenousDNA is limited to about 4.5 kb. Methods for producing and using suchAAVs are known in the art. See, for example, U.S. Pat. Nos. 5,139,941,5,173,414, 5,354,678, 5,436,146, 5,474,935, 5,478,745, and 5,589,377.

For example, an appropriate AAV vector for use in the present inventionwill include all the sequences necessary for DNA replication,encapsidation, and host-cell integration. The polynucleotide constructis inserted into the AAV vector using standard cloning methods, such asthose found in Sambrook et al., Molecular Cloning: A Laboratory Manual,Cold Spring Harbor Press (1989). The recombinant AAV vector is thentransfected into packaging cells which are infected with a helper virus,using any standard technique, including lipofection, electroporation,calcium phosphate precipitation, etc. Appropriate helper viruses includeadenoviruses, cytomegaloviruses, vaccinia viruses, or herpes viruses.Once the packaging cells are transfected and infected, they will produceinfectious AAV viral particles which contain the polynucleotideconstruct. These viral particles are then used to transduce eukaryoticcells, either ex vivo or in vivo. The transduced cells will contain thepolynucleotide construct integrated into its genome, and will express apolypeptide of the invention.

Another method of gene therapy involves operably associatingheterologous control regions and endogenous polynucleotide sequences(e.g. encoding a polypeptide of the present invention) via homologousrecombination (see, e.g., U.S. Pat. No. 5,641,670, issued Jun. 24, 1997;International Publication No. WO 96/29411, published Sep. 26, 1996;International Publication No. WO 94/12650, published Aug. 4, 1994;Koller et al., Proc. Natl. Acad. Sci. USA 86:8932-8935 (1989); andZijlstra et al., Nature 342:435-438 (1989), which are hereinencorporated by reference. This method involves the activation of a genewhich is present in the target cells, but which is not normallyexpressed in the cells, or is expressed at a lower level than desired.

Polynucleotide constructs are made, using standard techniques known inthe art, which contain the promoter with targeting sequences flankingthe promoter. Suitable promoters are described herein. The targetingsequence is sufficiently complementary to an endogenous sequence topermit homologous recombination of the promoter-targeting sequence withthe endogenous sequence. The targeting sequence will be sufficientlynear the 5′ end of the desired endogenous polynucleotide sequence so thepromoter will be operably linked to the endogenous sequence uponhomologous recombination.

The promoter and the targeting sequences can be amplified using PCR.Preferably, the amplified promoter contains distinct restriction enzymesites on the 5′ and 3′ ends. Preferably, the 3′ end of the firsttargeting sequence contains the same restriction enzyme site as the 5′end of the amplified promoter and the 5′ end of the second targetingsequence contains the same restriction site as the 3′ end of theamplified promoter. The amplified promoter and targeting sequences aredigested and ligated together.

The promoter-targeting sequence construct is delivered to the cells,either as naked polynucleotide, or in conjunction withtransfection-facilitating agents, such as liposomes, viral sequences,viral particles, whole viruses, lipofection, precipitating agents, etc.,described in more detail above. The P promoter-targeting sequence can bedelivered by any method, included direct needle injection, intravenousinjection, topical administration, catheter infusion, particleaccelerators, etc. The methods are described in more detail below.

The promoter-targeting sequence construct is taken up by cells.Homologous recombination between the construct and the endogenoussequence takes place, such that an endogenous sequence is placed underthe control of the promoter. The promoter then drives the expression ofthe endogenous sequence.

The polynucleotide encoding a polypeptide of the present invention maycontain a secretory signal sequence that facilitates secretion of theprotein. Typically, the signal sequence is positioned in the codingregion of the polynucleotide to be expressed towards or at the 5′ end ofthe coding region. The signal sequence may be homologous or heterologousto the polynucleotide of interest and may be homologous or heterologousto the cells to be transfected. Additionally, the signal sequence may bechemically synthesized using methods known in the art.

Any mode of administration of any of the above-described polynucleotidesconstructs can be used so long as the mode results in the expression ofone or more molecules in an amount sufficient to provide a therapeuticeffect. This includes direct needle injection, systemic injection,catheter infusion, biolistic injectors, particle accelerators (i.e.,“gene guns”), gelfoam sponge depots, other commercially available depotmaterials, osmotic pumps (e.g., Alza minipumps), oral or suppositorialsolid (tablet or pill) pharmaceutical formulations, and decanting ortopical applications during surgery. For example, direct injection ofnaked calcium phosphate-precipitated plasmid into rat liver and ratspleen or a protein-coated plasmid into the portal vein has resulted ingene expression of the foreign gene in the rat livers (Kaneda et al.,Science 243:375 (1989)).

A preferred method of local administration is by direct injection.Preferably, a recombinant molecule of the present invention complexedwith a delivery vehicle is administered by direct injection into orlocally within the area of arteries. Administration of a compositionlocally within the area of arteries refers to injecting the compositioncentimeters and preferably, millimeters within arteries.

Another method of local administration is to contact a polynucleotideconstruct of the present invention in or around a surgical wound. Forexample, a patient can undergo surgery and the polynucleotide constructcan be coated on the surface of tissue inside the wound or the constructcan be injected into areas of tissue inside the wound.

Therapeutic compositions useful in systemic administration, includerecombinant molecules of the present invention complexed to a targeteddelivery vehicle of the present invention. Suitable delivery vehiclesfor use with systemic administration comprise liposomes comprisingligands for targeting the vehicle to a particular site. In specificembodiments, suitable delivery vehicles for use with systemicadministration comprise liposomes comprising polypeptides of theinvention for targeting the vehicle to a particular site.

Preferred methods of systemic administration, include intravenousinjection, aerosol, oral and percutaneous (topical) delivery.Intravenous injections can be performed using methods standard in theart. Aerosol delivery can also be performed using methods standard inthe art (see, for example, Stribling et al., Proc. Natl. Acad. Sci. USA189:11277-11281, 1992, which is incorporated herein by reference). Oraldelivery can be performed by complexing a polynucleotide construct ofthe present invention to a carrier capable of withstanding degradationby digestive enzymes in the gut of an animal. Examples of such carriers,include plastic capsules or tablets, such as those known in the art.Topical delivery can be performed by mixing a polynucleotide constructof the present invention with a lipophilic reagent (e.g., DMSO) that iscapable of passing into the skin.

Determining an effective amount of substance to be delivered can dependupon a number of factors including, for example, the chemical structureand biological activity of the substance, the age and weight of theanimal, the precise condition requiring treatment and its severity, andthe route of administration. The frequency of treatments depends upon anumber of factors, such as the amount of polynucleotide constructsadministered per dose, as well as the health and history of the subject.The precise amount, number of doses, and timing of doses will bedetermined by the attending physician or veterinarian.

Therapeutic compositions of the present invention can be administered toany animal, preferably to mammals and birds. Preferred mammals includehumans, dogs, cats, mice, rats, rabbits sheep, cattle, horses and pigs,with humans being particularly preferred.

Biological Activities

Polynucleotides or polypeptides, or agonists or antagonists of thepresent invention, can be used in assays to test for one or morebiological activities. If these polynucleotides or polypeptides, oragonists or antagonists of the present invention, do exhibit activity ina particular assay, it is likely that these molecules may be involved inthe diseases associated with the biological activity. Thus, thepolynucleotides and polypeptides, and agonists or antagonists could beused to treat the associated disease.

Members of the secreted family of proteins are believed to be involvedin biological activities associated with, for example, cellularsignaling. Accordingly, compositions of the invention (includingpolynucleotides, polypeptides and antibodies of the invention, andfragments and variants thereof) may be used in diagnosis, prognosis,prevention and/or treatment of diseases and/or disorders associated withaberrant activity of secreted polypeptides.

In preferred embodiments, compositions of the invention (includingpolynucleotides, polypeptides and antibodies of the invention, andfragments and variants thereof) may be used in the diagnosis, prognosis,prevention, treatment, and/or amelioration of diseases and/or disordersrelating to the cardiovascular system (e.g., atherosclerosis, stroke,myocardial infarction, hypertension, and as described in the“Cardiovascular Disorders” section below).

In certain embodiments, a polypeptide of the invention, orpolynucleotides, antibodies, agonists, or antagonists corresponding tothat polypeptide, may be used to diagnose and/or prognosticate diseasesand/or disorders associated with the tissue(s) in which the polypeptideof the invention is expressed including one, two, three, four, five, ormore tissues disclosed in Table 1B.2 (Tissue Distribution Library Code).

Thus, polynucleotides, translation products and antibodies of theinvention are useful in the diagnosis, detection, prevention,prognistication, and/or treatment of diseases and/or disordersassociated with activities that include, but are not limited to,prohormone activation, neurotransmitter activity, cellular signaling,cellular proliferation, cellular differentiation, and cell migration.

More generally, polynucleotides, translation products and antibodiescorresponding to this gene may be useful for the diagnosis, prognosis,prevention, treatment and/or amelioration of diseases and/or disordersassociated with the following system or systems.

Cardiovascular Disorders

Polynucleotides or polypeptides, or agonists or antagonists of thepresent invention, may be used to detect, prevent, diagnose,prognosticate, treat, and/or ameliorate cardiovascular diseases anddisorders, including, but not limited to, peripheral artery disease,such as limb ischemia.

Cardiovascular disorders include, but are not limited to, cardiovascularabnormalities, such as arterio-arterial fistula, arteriovenous fistula,cerebral arteriovenous malformations, congenital heart defects,pulmonary atresia, and Scimitar Syndrome. Congenital heart defectsinclude, but are not limited to, aortic coarctation, cor triatriatum,coronary vessel anomalies, crisscross heart, dextrocardia, patent ductusarteriosus, Ebstein's anomaly, Eisenmenger complex, hypoplastic leftheart syndrome, levocardia, tetralogy of fallot, transposition of greatvessels, double outlet right ventricle, tricuspid atresia, persistenttruncus arteriosus, and heart septal defects, such as aortopulmonaryseptal defect, endocardial cushion defects, Lutembacher's Syndrome,trilogy of Fallot, ventricular heart septal defects.

Cardiovascular disorders also include, but are not limited to, heartdisease, such as arrhythmias, carcinoid heart disease, high cardiacoutput, low cardiac output, cardiac tamponade, endocarditis (includingbacterial), heart aneurysm, cardiac arrest, congestive heart failure,congestive cardiomyopathy, paroxysmal dyspnea, cardiac edema, hearthypertrophy, congestive cardiomyopathy, left ventricular hypertrophy,right ventricular hypertrophy, post-infarction heart rupture,ventricular septal rupture, heart valve diseases, myocardial diseases,myocardial ischemia, pericardial effusion, pericarditis (includingconstrictive and tuberculous), pneumopericardium, postpericardiotomysyndrome, pulmonary heart disease, rheumatic heart disease, ventriculardysfunction, hyperemia, cardiovascular pregnancy complications, ScimitarSyndrome, cardiovascular syphilis, and cardiovascular tuberculosis.

Arrhythmias include, but are not limited to, sinus arrhythmia, atrialfibrillation, atrial flutter, bradycardia, extrasystole, Adams-StokesSyndrome, bundle-branch block, sinoatrial block, long QT syndrome,parasystole, Lown-Ganong-Levine Syndrome, Mahaim-type pre-excitationsyndrome, Wolff-Parkinson-White syndrome, sick sinus syndrome,tachycardias, and ventricular fibrillation. Tachycardias includeparoxysmal tachycardia, supraventricular tachycardia, acceleratedidioventricular rhythm, atrioventricular nodal reentry tachycardia,ectopic atrial tachycardia, ectopic junctional tachycardia, sinoatrialnodal reentry tachycardia, sinus tachycardia, Torsades de Pointes, andventricular tachycardia.

Heart valve diseases include, but are not limited to, aortic valveinsufficiency, aortic valve stenosis, hear murmurs, aortic valveprolapse, mitral valve prolapse, tricuspid valve prolapse, mitral valveinsufficiency, mitral valve stenosis, pulmonary atresia, pulmonary valveinsufficiency, pulmonary valve stenosis, tricuspid atresia, tricuspidvalve insufficiency, and tricuspid valve stenosis.

Myocardial diseases include, but are not limited to, alcoholiccardiomyopathy, congestive cardiomyopathy, hypertrophic cardiomyopathy,aortic subvalvular stenosis, pulmonary subvalvular stenosis, restrictivecardiomyopathy, Chagas cardiomyopathy, endocardial fibroelastosis,endomyocardial fibrosis, Kearns Syndrome, myocardial reperfusion injury,and myocarditis.

Myocardial ischemias include, but are not limited to, coronary disease,such as angina pectoris, coronary aneurysm, coronary arteriosclerosis,coronary thrombosis, coronary vasospasm, myocardial infarction andmyocardial stunning.

Cardiovascular diseases also include vascular diseases such asaneurysms, angiodysplasia, angiomatosis, bacillary angiomatosis,Hippel-Lindau Disease, Klippel-Trenaunay-Weber Syndrome, Sturge-WeberSyndrome, angioneurotic edema, aortic diseases, Takayasu's Arteritis,aortitis, Leriche's Syndrome, arterial occlusive diseases, arteritis,enarteritis, polyarteritis nodosa, cerebrovascular disorders, diabeticangiopathies, diabetic retinopathy, embolisms, thrombosis,erythromelalgia, hemorrhoids, hepatic veno-occlusive disease,hypertension, hypotension, ischemia, peripheral vascular diseases,phlebitis, pulmonary veno-occlusive disease, Raynaud's disease, CRESTsyndrome, retinal vein occlusion, Scimitar syndrome, superior vena cavasyndrome, telangiectasia, atacia telangiectasia, hereditary hemorrhagictelangiectasia, varicocele, varicose veins, varicose ulcer, vasculitis,and venous insufficiency.

Aneurysms include, but are not limited to, dissecting aneurysms, falseaneurysms, infected aneurysms, ruptured aneurysms, aortic aneurysms,cerebral aneurysms, coronary aneurysms, heart aneurysms, and iliacaneurysms.

Arterial occlusive diseases include, but are not limited to,arteriosclerosis, intermittent claudication, carotid stenosis,fibromuscular dysplasias, mesenteric vascular occlusion, Moyamoyadisease, renal artery obstruction, retinal artery occlusion, andthromboangiitis obliterans.

Cerebrovascular disorders include, but are not limited to, carotidartery diseases, cerebral amyloid angiopathy, cerebral aneurysm,cerebral anoxia, cerebral arteriosclerosis, cerebral arteriovenousmalformation, cerebral artery diseases, cerebral embolism andthrombosis, carotid artery thrombosis, sinus thrombosis, Wallenberg'ssyndrome, cerebral hemorrhage, epidural hematoma, subdural hematoma,subaraxrhnoid hemorrhage, cerebral infarction, cerebral ischemia(including transient), subclavian steal syndrome, periventricularleukomalacia, vascular headache, cluster headache, migraine, andvertebrobasilar insufficiency.

Embolisms include, but are not limited to, air embolisms, amniotic fluidembolisms, cholesterol embolisms, blue toe syndrome, fat embolisms,pulmonary embolisms, and thromoboembolisms. Thrombosis include, but arenot limited to, coronary thrombosis, hepatic vein thrombosis, retinalvein occlusion, carotid artery thrombosis, sinus thrombosis,Wallenberg's syndrome, and thrombophlebitis.

Ischemic disorders include, but are not limited to, cerebral ischemia,ischemic colitis, compartment syndromes, anterior compartment syndrome,myocardial ischemia, reperfusion injuries, and peripheral limb ischemia.Vasculitis includes, but is not limited to, aortitis, arteritis,Behcet's Syndrome, Churg-Strauss Syndrome, mucocutaneous lymph nodesyndrome, thromboangiitis obliterans, hypersensitivity vasculitis,Schoenlein-Henoch purpura, allergic cutaneous vasculitis, and Wegener'sgranulomatosis.

Polypeptides may be administered using any method known in the art,including, but not limited to, direct needle injection at the deliverysite, intravenous injection, topical administration, catheter infusion,biolistic injectors, particle accelerators, gelfoam sponge depots, othercommercially available depot materials, osmotic pumps, oral orsuppositorial solid pharmaceutical formulations, decanting or topicalapplications during surgery, aerosol delivery. Such methods are known inthe art. Polypeptides may be administered as part of a Therapeutic,described in more detail below. Methods of delivering polynucleotidesare described in more detail herein.

Wound Healing and Epithelial Cell Proliferation

In accordance with yet a further aspect of the present invention, thereis provided a process for utilizing polynucleotides or polypeptides, aswell as agonists or antagonists of the present invention, fortherapeutic purposes, for example, to stimulate epithelial cellproliferation and basal keratinocytes for the purpose of wound healing,and to stimulate hair follicle production and healing of dermal wounds.Polynucleotides or polypeptides, as well as agonists or antagonists ofthe present invention, may be clinically useful in stimulating woundhealing including surgical wounds, excisional wounds, deep woundsinvolving damage of the dermis and epidermis, eye tissue wounds, dentaltissue wounds, oral cavity wounds, diabetic ulcers, dermal ulcers,cubitus ulcers, arterial ulcers, venous stasis ulcers, burns resultingfrom heat exposure or chemicals, and other abnormal wound healingconditions such as uremia, malnutrition, vitamin deficiencies andcomplications associated with systemic treatment with steroids,radiation therapy and antineoplastic drugs and antimetabolites.Polynucleotides or polypeptides, as well as agonists or antagonists ofthe present invention, could be used to promote dermal reestablishmentsubsequent to dermal loss

Polynucleotides or polypeptides, as well as agonists or antagonists ofthe present invention, could be used to increase the adherence of skingrafts to a wound bed and to stimulate re-epithelialization from thewound bed. The following are types of grafts that polynucleotides orpolypeptides, agonists or antagonists of the present invention, could beused to increase adherence to a wound bed: autografts, artificial skin,allografts, autodermic graft, autoepdermic grafts, avacular grafts,Blair-Brown grafts, bone graft, brephoplastic grafts, cutis graft,delayed graft, dermic graft, epidermic graft, fascia graft, fullthickness graft, heterologous graft, xenograft, homologous graft,hyperplastic graft, lamellar graft, mesh graft, mucosal graft,Ollier-Thiersch graft, omenpal graft, patch graft, pedicle graft,penetrating graft, split skin graft, thick split graft. Polynucleotidesor polypeptides, as well as agonists or antagonists of the presentinvention, can be used to promote skin strength and to improve theappearance of aged skin.

It is believed that polynucleotides or polypeptides, as well as agonistsor antagonists of the present invention, will also produce changes inhepatocyte proliferation, and epithelial cell proliferation in the lung,breast, pancreas, stomach, small intestine, and large intestine.Polynucleotides or polypeptides, as well as agonists or antagonists ofthe present invention, could promote proliferation of epithelial cellssuch as sebocytes, hair follicles, hepatocytes, type II pneumocytes,mucin-producing goblet cells, and other epithelial cells and theirprogenitors contained within the skin, lung, liver, and gastrointestinaltract. Polynucleotides or polypeptides, agonists or antagonists of thepresent invention, may promote proliferation of endothelial cells,keratinocytes, and basal keratinocytes.

Polynucleotides or polypeptides, as well as agonists or antagonists ofthe present invention, could also be used to reduce the side effects ofgut toxicity that result from radiation, chemotherapy treatments orviral infections. Polynucleotides or polypeptides, as well as agonistsor antagonists of the present invention, may have a cytoprotectiveeffect on the small intestine mucosa. Polynucleotides or polypeptides,as well as agonists or antagonists of the present invention, may alsostimulate healing of mucositis (mouth ulcers) that result fromchemotherapy and viral infections.

Polynucleotides or polypeptides, as well as agonists or antagonists ofthe present invention, could further be used in full regeneration ofskin in full and partial thickness skin defects, including burns, (i.e.,repopulation of hair follicles, sweat glands, and sebaceous glands),treatment of other skin defects such as psoriasis. Polynucleotides orpolypeptides, as well as agonists or antagonists of the presentinvention, could be used to treat epidermolysis bullosa, a defect inadherence of the epidermis to the underlying dermis which results infrequent, open and painful blisters by accelerating reepithelializationof these lesions. Polynucleotides or polypeptides, as well as agonistsor antagonists of the present invention, could also be used to treatgastric and doudenal ulcers and help heal by scar formation of themucosal lining and regeneration of glandular mucosa and duodenal mucosallining more rapidly. Inflammatory bowel diseases, such as Crohn'sdisease and ulcerative colitis, are diseases which result in destructionof the mucosal surface of the small or large intestine, respectively.Thus, polynucleotides or polypeptides, as well as agonists orantagonists of the present invention, could be used to promote theresurfacing of the mucosal surface to aid more rapid healing and toprevent progression of inflammatory bowel disease. Treatment withpolynucleotides or polypeptides, agonists or antagonists of the presentinvention, is expected to have a significant effect on the production ofmucus throughout the gastrointestinal tract and could be used to protectthe intestinal mucosa from injurious substances that are ingested orfollowing surgery. Polynucleotides or polypeptides, as well as agonistsor antagonists of the present invention, could be used to treat diseasesassociate with the under expression.

Moreover, polynucleotides or polypeptides, as well as agonists orantagonists of the present invention, could be used to prevent and healdamage to the lungs due to various pathological states. Polynucleotidesor polypeptides, as well as agonists or antagonists of the presentinvention, which could stimulate proliferation and differentiation andpromote the repair of alveoli and brochiolar epithelium to prevent ortreat acute or chronic lung damage. For example, emphysema, whichresults in the progressive loss of aveoli, and inhalation injuries,i.e., resulting from smoke inhalation and burns, that cause necrosis ofthe bronchiolar epithelium and alveoli could be effectively treatedusing polynucleotides or polypeptides, agonists or antagonists of thepresent invention. Also, polynucleotides or polypeptides, as well asagonists or antagonists of the present invention, could be used tostimulate the proliferation of and differentiation of type IIpneumocytes, which may help treat or prevent disease such as hyalinemembrane diseases, such as infant respiratory distress syndrome andbronchopulmonary displasia, in premature infants.

Polynucleotides or polypeptides, as well as agonists or antagonists ofthe present invention, could stimulate the proliferation anddifferentiation of hepatocytes and, thus, could be used to alleviate ortreat liver diseases and pathologies such as fulminant liver failurecaused by cirrhosis, liver damage caused by viral hepatitis and toxicsubstances (i.e., acetaminophen, carbon tetraholoride and otherhepatotoxins known in the art).

In addition, polynucleotides or polypeptides, as well as agonists orantagonists of the present invention, could be used treat or prevent theonset of diabetes mellitus. In patients with newly diagnosed Types I andII diabetes, where some islet cell function remains, polynucleotides orpolypeptides, as well as agonists or antagonists of the presentinvention, could be used to maintain the islet function so as toalleviate, delay or prevent permanent manifestation of the disease.Also, polynucleotides or polypeptides, as well as agonists orantagonists of the present invention, could be used as an auxiliary inislet cell transplantation to improve or promote islet cell function.

Chemotaxis

Polynucleotides or polypeptides, as well as agonists or antagonists ofthe present invention may have chemotaxis activity. A chemotaxicmolecule attracts or mobilizes cells (e.g., monocytes, fibroblasts,neutrophils, T-cells, mast cells, eosinophils, epithelial and/orendothelial cells) to a particular site in the body, such asinflammation, infection, or site of hyperproliferation. The mobilizedcells can then fight off and/or heal the particular trauma orabnormality.

Polynucleotides or polypeptides, as well as agonists or antagonists ofthe present invention may increase chemotaxic activity of particularcells. These chemotactic molecules can then be used to treatinflammation, infection, hyperproliferative disorders, or any immunesystem disorder by increasing the number of cells targeted to aparticular location in the body. For example, chemotaxic molecules canbe used to treat wounds and other trauma to tissues by attracting immunecells to the injured location. Chemotactic molecules of the presentinvention can also attract fibroblasts, which can be used to treatwounds.

It is also contemplated that polynucleotides or polypeptides, as well asagonists or antagonists of the present invention may inhibit chemotacticactivity. These molecules could also be used to treat disorders. Thus,polynucleotides or polypeptides, as well as agonists or antagonists ofthe present invention could be used as an inhibitor of chemotaxis.

Binding Activity

A polypeptide of the present invention may be used to screen formolecules that bind to the polypeptide or for molecules to which thepolypeptide binds. The binding of the polypeptide and the molecule mayactivate (agonist), increase, inhibit (antagonist), or decrease activityof the polypeptide or the molecule bound. Examples of such moleculesinclude antibodies, oligonucleotides, proteins (e.g., receptors), orsmall molecules.

Preferably, the molecule is closely related to the natural ligand of thepolypeptide, e.g., a fragment of the ligand, or a natural substrate, aligand, a structural or functional mimetic. (See, Coligan et al.,Current Protocols in Immunology 1(2):Chapter 5 (1991)). Similarly, themolecule can be closely related to the natural receptor to which thepolypeptide binds, or at least, a fragment of the receptor capable ofbeing bound by the polypeptide (e.g., active site). In either case, themolecule can be rationally designed using known techniques.

Preferably, the screening for these molecules involves producingappropriate cells which express the polypeptide. Preferred cells includecells from mammals, yeast, Drosophila, or E. coli. Cells expressing thepolypeptide (or cell membrane containing the expressed polypeptide) arethen preferably contacted with a test compound potentially containingthe molecule to observe binding, stimulation, or inhibition of activityof either the polypeptide or the molecule.

The assay may simply test binding of a candidate compound to thepolypeptide, wherein binding is detected by a label, or in an assayinvolving competition with a labeled competitor. Further, the assay maytest whether the candidate compound results in a signal generated bybinding to the polypeptide.

Alternatively, the assay can be carried out using cell-freepreparations, polypeptide/molecule affixed to a solid support, chemicallibraries, or natural product mixtures. The assay may also simplycomprise the steps of mixing a candidate compound with a solutioncontaining a polypeptide, measuring polypeptide/molecule activity orbinding, and comparing the polypeptide/molecule activity or binding to astandard.

Preferably, an ELISA assay can measure polypeptide level or activity ina sample (e.g., biological sample) using a monoclonal or polyclonalantibody. The antibody can measure polypeptide level or activity byeither binding, directly or indirectly, to the polypeptide or bycompeting with the polypeptide for a substrate.

Additionally, the receptor to which the polypeptide of the presentinvention binds can be identified by numerous methods known to those ofskill in the art, for example, ligand panning and FACS sorting (Coligan,et al., Current Protocols in Immun., 1(2), Chapter 5, (1991)). Forexample, expression cloning is employed wherein polyadenylated RNA isprepared from a cell responsive to the polypeptides, for example, NIH3T3cells which are known to contain multiple receptors for the FGF familyproteins, and SC-3 cells, and a cDNA library created from this RNA isdivided into pools and used to transfect COS cells or other cells thatare not responsive to the polypeptides. Transfected cells which aregrown on glass slides are exposed to the polypeptide of the presentinvention, after they have been labeled. The polypeptides can be labeledby a variety of means including iodination or inclusion of a recognitionsite for a site-specific protein kinase.

Following fixation and incubation, the slides are subjected toauto-radiographic analysis. Positive pools are identified and sub-poolsare prepared and re-transfected using an iterative sub-pooling andre-screening process, eventually yielding a single clones that encodesthe putative receptor.

As an alternative approach for receptor identification, the labeledpolypeptides can be photoaffinity linked with cell membrane or extractpreparations that express the receptor molecule. Cross-linked materialis resolved by PAGE analysis and exposed to X-ray film. The labeledcomplex containing the receptors of the polypeptides can be excised,resolved into peptide fragments, and subjected to proteinmicrosequencing. The amino acid sequence obtained from microsequencingwould be used to design a set of degenerate oligonucleotide probes toscreen a cDNA library to identify the genes encoding the putativereceptors.

Moreover, the techniques of gene-shuffling, motif-shuffling,exon-shuffling, and/or codon-shuffling (collectively referred to as “DNAshuffling”) may be employed to modulate the activities of thepolypeptide of the present invention thereby effectively generatingagonists and antagonists of the polypeptide of the present invention.See generally, U.S. Pat. Nos. 5,605,793, 5,811,238, 5,830,721,5,834,252, and 5,837,458, and Patten, P. A., et al., Curr. OpinionBiotechnol. 8:724-33 (1997); Harayama, S. Trends Biotechnol. 16(2):76-82(1998); Hansson, L. O., et al., J. Mol. Biol. 287:265-76 (1999); andLorenzo, M. M. and Blasco, R. Biotechniques 24(2):308-13 (1998); each ofthese patents and publications are hereby incorporated by reference). Inone embodiment, alteration of polynucleotides and correspondingpolypeptides may be achieved by DNA shuffling. DNA shuffling involvesthe assembly of two or more DNA segments into a desired molecule byhomologous, or site-specific, recombination. In another embodiment,polynucleotides and corresponding polypeptides may be altered by beingsubjected to random mutagenesis by error-prone PCR, random nucleotideinsertion or other methods prior to recombination. In anotherembodiment, one or more components, motifs, sections, parts, domains,fragments, etc., of the polypeptide of the present invention may berecombined with one or more components, motifs, sections, parts,domains, fragments, etc. of one or more heterologous molecules. Inpreferred embodiments, the heterologous molecules are family members. Infurther preferred embodiments, the heterologous molecule is a growthfactor such as, for example, platelet-derived growth factor (PDGF),insulin-like growth factor (IGF-I), transforming growth factor(TGF)-alpha, epidermal growth factor (EGF), fibroblast growth factor(FGF), TGF-beta, bone morphogenetic protein (BMP)-2, BMP-4, BMP-5,BMP-6, BMP-7, activins A and B, decapentaplegic(dpp), 60A, OP-2,dorsalin, growth differentiation factors (GDFs), nodal, MIS,inhibin-alpha, TGF-beta1, TGF-beta2, TGF-beta3, TGF-beta5, andglial-derived neurotrophic factor (GDNF).

Other preferred fragments are biologically active fragments of thepolypeptide of the present invention. Biologically active fragments arethose exhibiting activity similar, but not necessarily identical, to anactivity of the polypeptide of the present invention. The biologicalactivity of the fragments may include an improved desired activity, or adecreased undesirable activity.

Additionally, this invention provides a method of screening compounds toidentify those which modulate the action of the polypeptide of thepresent invention. An example of such an assay comprises combining amammalian fibroblast cell, a the polypeptide of the present invention,the compound to be screened and ³[H] thymidine under cell cultureconditions where the fibroblast cell would normally proliferate. Acontrol assay may be performed in the absence of the compound to bescreened and compared to the amount of fibroblast proliferation in thepresence of the compound to determine if the compound stimulatesproliferation by determining the uptake of ³[H] thymidine in each case.The amount of fibroblast cell proliferation is measured by liquidscintillation chromatography which measures the incorporation of ³[H]thymidine. Both agonist and antagonist compounds may be identified bythis procedure.

In another method, a mammalian cell or membrane preparation expressing areceptor for a polypeptide of the present invention is incubated with alabeled polypeptide of the present invention in the presence of thecompound. The ability of the compound to enhance or block thisinteraction could then be measured. Alternatively, the response of aknown second messenger system following interaction of a compound to bescreened and the receptor is measured and the ability of the compound tobind to the receptor and elicit a second messenger response is measuredto determine if the compound is a potential agonist or antagonist. Suchsecond messenger systems include but are not limited to, cAMP guanylatecyclase, ion channels or phosphoinositide hydrolysis.

All of these above assays can be used as diagnostic or prognosticmarkers. The molecules discovered using these assays can be used totreat disease or to bring about a particular result in a patient (e.g.,blood vessel growth) by activating or inhibiting thepolypeptide/molecule. Moreover, the assays can discover agents which mayinhibit or enhance the production of the polypeptides of the inventionfrom suitably manipulated cells or tissues.

Therefore, the invention includes a method of identifying compoundswhich bind to a polypeptide of the invention comprising the steps of:(a) incubating a candidate binding compound with a polypeptide of thepresent invention; and (b) determining if binding has occurred.Moreover, the invention includes a method of identifyingagonists/antagonists comprising the steps of: (a) incubating a candidatecompound with a polypeptide of the present invention, (b) assaying abiological activity, and (b) determining if a biological activity of thepolypeptide has been altered.

Targeted Delivery

In another embodiment, the invention provides a method of deliveringcompositions to targeted cells expressing a receptor for a polypeptideof the invention, or cells expressing a cell bound form of a polypeptideof the invention.

As discussed herein, polypeptides or antibodies of the invention may beassociated with heterologous polypeptides, heterologous nucleic acids,toxins, or prodrugs via hydrophobic, hydrophilic, ionic and/or covalentinteractions. In one embodiment, the invention provides a method for thespecific delivery of compositions of the invention to cells byadministering polypeptides of the invention (including antibodies) thatare associated with heterologous polypeptides or nucleic acids. In oneexample, the invention provides a method for delivering a therapeuticprotein into the targeted cell. In another example, the inventionprovides a method for delivering a single stranded nucleic acid (e.g.,antisense or ribozymes) or double stranded nucleic acid (e.g., DNA thatcan integrate into the cell's genome or replicate episomally and thatcan be transcribed) into the targeted cell.

In another embodiment, the invention provides a method for the specificdestruction of cells (e.g., the destruction of tumor cells) byadministering polypeptides of the invention (e.g., polypeptides of theinvention or antibodies of the invention) in association with toxins orcytotoxic prodrugs.

By “toxin” is meant compounds that bind and activate endogenouscytotoxic effector systems, radioisotopes, holotoxins, modified toxins,catalytic subunits of toxins, or any molecules or enzymes not normallypresent in or on the surface of a cell that under defined conditionscause the cell's death. Toxins that may be used according to the methodsof the invention include, but are not limited to, radioisotopes known inthe art, compounds such as, for example, antibodies (or complementfixing containing portions thereof) that bind an inherent or inducedendogenous cytotoxic effector system, thymidine kinase, endonuclease,RNAse, alpha toxin, ricin, abrin, Pseudomonas exotoxin A, diphtheriatoxin, saporin, momordin, gelonin, pokeweed antiviral protein,alpha-sarcin and cholera toxin. By “cytotoxic prodrug” is meant anon-toxic compound that is converted by an enzyme, normally present inthe cell, into a cytotoxic compound. Cytotoxic prodrugs that may be usedaccording to the methods of the invention include, but are not limitedto, glutamyl derivatives of benzoic acid mustard alkylating agent,phosphate derivatives of etoposide or mitomycin C, cytosine arabinoside,daunorubisin, and phenoxyacetamide derivatives of doxorubicin.

Drug Screening

Further contemplated is the use of the polypeptides of the presentinvention, or the polynucleotides encoding these polypeptides, to screenfor molecules which modify the activities of the polypeptides of thepresent invention. Such a method would include contacting thepolypeptide of the present invention with a selected compound(s)suspected of having antagonist or agonist activity, and assaying theactivity of these polypeptides following binding.

This invention is particularly useful for screening therapeuticcompounds by using the polypeptides of the present invention, or bindingfragments thereof, in any of a variety of drug screening techniques. Thepolypeptide or fragment employed in such a test may be affixed to asolid support, expressed on a cell surface, free in solution, or locatedintracellularly. One method of drug screening utilizes eukaryotic orprokaryotic host cells which are stably transformed with recombinantnucleic acids expressing the polypeptide or fragment. Drugs are screenedagainst such transformed cells in competitive binding assays. One maymeasure, for example, the formulation of complexes between the agentbeing tested and a polypeptide of the present invention.

Thus, the present invention provides methods of screening for drugs orany other agents which affect activities mediated by the polypeptides ofthe present invention. These methods comprise contacting such an agentwith a polypeptide of the present invention or a fragment thereof andassaying for the presence of a complex between the agent and thepolypeptide or a fragment thereof, by methods well known in the art. Insuch a competitive binding assay, the agents to screen are typicallylabeled. Following incubation, free agent is separated from that presentin bound form, and the amount of free or uncomplexed label is a measureof the ability of a particular agent to bind to the polypeptides of thepresent invention.

Another technique for drug screening provides high throughput screeningfor compounds having suitable binding affinity to the polypeptides ofthe present invention, and is described in great detail in EuropeanPatent Application 84/03564, published on Sep. 13, 1984, which isincorporated herein by reference herein. Briefly stated, large numbersof different small peptide test compounds are synthesized on a solidsubstrate, such as plastic pins or some other surface. The peptide testcompounds are reacted with polypeptides of the present invention andwashed. Bound polypeptides are then detected by methods well known inthe art. Purified polypeptides are coated directly onto plates for usein the aforementioned drug screening techniques. In addition,non-neutralizing antibodies may be used to capture the peptide andimmobilize it on the solid support.

This invention also contemplates the use of competitive drug screeningassays in which neutralizing antibodies capable of binding polypeptidesof the present invention specifically compete with a test compound forbinding to the polypeptides or fragments thereof. In this manner, theantibodies are used to detect the presence of any peptide which sharesone or more antigenic epitopes with a polypeptide of the invention.

Antisense And Ribozyme (Antagonists)

In specific embodiments, antagonists according to the present inventionare nucleic acids corresponding to the sequences contained in SEQ IDNO:X, or the complementary strand thereof, and/or to cDNA sequencescontained in cDNA ATCC Deposit No:Z identified for example, in Table 1Aand/or 1B. In one embodiment, antisense sequence is generatedinternally, by the organism, in another embodiment, the antisensesequence is separately administered (see, for example, O'Connor, J.,Neurochem 56:560 (1991). Oligodeoxynucleotides as Antisense Inhibitorsof Gene Expression, CRC Press, Boca Raton, Fla. (1988). Antisensetechnology can be used to control gene expression through antisense DNAor RNA, or through triple-helix formation. Antisense techniques arediscussed for example, in Okano, J., Neurochem. 56:560 (1991);Oligodeoxynucleotides as Antisense Inhibitors of Gene Expression, CRCPress, Boca Raton, Fla. (1988). Triple helix formation is discussed in,for instance, Lee et al., Nucleic Acids Research 6:3073 (1979); Cooneyet al., Science 241:456 (1988); and Dervan et al., Science 251:1300(1991). The methods are based on binding of a polynucleotide to acomplementary DNA or RNA.

For example, the use of c-myc and c-myb antisense RNA constructs toinhibit the growth of the non-lymphocytic leukemia cell line HL-60 andother cell lines was previously described. (Wickstrom et al. (1988);Anfossi et al. (1989)). These experiments were performed in vitro byincubating cells with the oligoribonucleotide. A similar procedure forin vivo use is described in WO 91/15580. Briefly, a pair ofoligonucleotides for a given antisense RNA is produced as follows: Asequence complimentary to the first 15 bases of the open reading frameis flanked by an EcOR1 site on the 5 end and a HindIII site on the 3end. Next, the pair of oligonucleotides is heated at 90° C. for oneminute and then annealed in 2× ligation buffer (20 mM TRIS HCl pH 7.5,10 mM MgCl2, 10 MM dithiothreitol (DTT) and 0.2 mM ATP) and then ligatedto the EcOR1/Hind m site of the retroviral vector PMV7 (WO 91/15580).

For example, the 5′ coding portion of a polynucleotide that encodes thepolypeptide of the present invention may be used to design an antisenseRNA oligonucleotide of from about 10 to 40 base pairs in length. A DNAoligonucleotide is designed to be complementary to a region of the geneinvolved in transcription thereby preventing transcription and theproduction of the receptor. The antisense RNA oligonucleotide hybridizesto the mRNA in vivo and blocks translation of the mRNA molecule intoreceptor polypeptide.

In one embodiment, the antisense nucleic acid of the invention isproduced intracellularly by transcription from an exogenous sequence.For example, a vector or a portion thereof, is transcribed, producing anantisense nucleic acid (RNA) of the invention. Such a vector wouldcontain a sequence encoding the antisense nucleic acid. Such a vectorcan remain episomal or become chromosomally integrated, as long as itcan be transcribed to produce the desired antisense RNA. Such vectorscan be constructed by recombinant DNA technology methods standard in theart. Vectors can be plasmid, viral, or others known in the art, used forreplication and expression in vertebrate cells. Expression of thesequence encoding the polypeptide of the present invention or fragmentsthereof, can be by any promoter known in the art to act in vertebrate,preferably human cells. Such promoters can be inducible or constitutive.Such promoters include, but are not limited to, the SV40 early promoterregion (Bernoist and Chambon, Nature 29:304-310 (1981), the promotercontained in the 3′ long terminal repeat of Rous sarcoma virus (Yamamotoet al., Cell 22:787-797 (1980), the herpes thymidine promoter (Wagner etal., Proc. Natl. Acad. Sci. U.S.A. 78:1441-1445 (1981), the regulatorysequences of the metallothionein gene (Brinster, et al., Nature 296:3942(1982)), etc.

The antisense nucleic acids of the invention comprise a sequencecomplementary to at least a portion of an RNA transcript of a gene ofthe present invention. However, absolute complementarity, althoughpreferred, is not required. A sequence “complementary to at least aportion of an RNA,” referred to herein, means a sequence havingsufficient complementarity to be able to hybridize with the RNA, forminga stable duplex; in the case of double stranded antisense nucleic acids,a single strand of the duplex DNA may thus be tested, or triplexformation may be assayed. The ability to hybridize will depend on boththe degree of complementarity and the length of the antisense nucleicacid. Generally, the larger the hybridizing nucleic acid, the more basemismatches with a RNA it may contain and still form a stable duplex (ortriplex as the case may be). One skilled in the art can ascertain atolerable degree of mismatch by use of standard procedures to determinethe melting point of the hybridized complex.

Oligonucleotides that are complementary to the 5′ end of the message,e.g., the 5′ untranslated sequence up to and including the AUGinitiation codon, should work most efficiently at inhibitingtranslation. However, sequences complementary to the 3′ untranslatedsequences of mRNAs have been shown to be effective at inhibitingtranslation of mRNAs as well. See generally, Wagner, R., 1994, Nature372:333-335. Thus, oligonucleotides complementary to either the 5′- or3′-non-translated, non-coding regions of polynucleotide sequencesdescribed herein could be used in an antisense approach to inhibittranslation of endogenous mRNA. Oligonucleotides complementary to the 5′untranslated region of the mRNA should include the complement of the AUGstart codon. Antisense oligonucleotides complementary to mRNA codingregions are less efficient inhibitors of translation but could be usedin accordance with the invention. Whether designed to hybridize to the5′-, 3′- or coding region of mRNA of the present invention, antisensenucleic acids should be at least six nucleotides in length, and arepreferably oligonucleotides ranging from 6 to about 50 nucleotides inlength. In specific aspects the oligonucleotide is at least 10nucleotides, at least 17 nucleotides, at least 25 nucleotides or atleast 50 nucleotides.

The polynucleotides of the invention can be DNA or RNA or chimericmixtures or derivatives or modified versions thereof, single-stranded ordouble-stranded. The oligonucleotide can be modified at the base moiety,sugar moiety, or phosphate backbone, for example, to improve stabilityof the molecule, hybridization, etc. The oligonucleotide may includeother appended groups such as peptides (e.g., for targeting host cellreceptors in vivo), or agents facilitating transport across the cellmembrane (see, e.g., Letsinger et al., 1989, Proc. Natl. Acad. Sci.U.S.A. 86:6553-6556; Lemaitre et al., 1987, Proc. Natl. Acad. Sci.84:648-652; PCT Publication No. WO88/09810, published Dec. 15, 1988) orthe blood-brain barrier (see, e.g., PCr Publication No. WO89/10134,published Apr. 25, 1988), hybridization-triggered cleavage agents. (See,e.g., Krol et al., 1988, BioTechniques 6:958-976) or intercalatingagents. (See, e.g., Zon, 1988, Pharm. Res. 5:539-549). To this end, theoligonucleotide may be conjugated to another molecule, e.g., a peptide,hybridization triggered cross-linking agent, transport agent,hybridization-triggered cleavage agent, etc.

The antisense oligonucleotide may comprise at least one modified basemoiety which is selected from the group including, but not limited to,5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil,hypoxanthine, xantine, 4-acetylcytosine, 5-carboxyhydroxylmethyl)uracil, 5-carboxymethylaminomethyl-2-thiouridine,5-carboxymethylaminomethyluracil, dihydrouracil,beta-D-galactosylqueosine, inosine, N6-isopentenyladenine,1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine,2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine,7-methylguanine, 5-methylaminomethyluracil,5-methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine,5′-methoxycarboxymethyluracil, 5-methoxyuracil,2-methylthio-N-6-isopentenyladenine, uracil-5-oxyacetic acid (v),wybutoxosine, pseudouracil, queosine, 2-thiocytosine,5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil,uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid (v),5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl) uracil, (acp3)w,and 2,6-diaminopurine.

The antisense oligonucleotide may also comprise at least one modifiedsugar moiety selected from the group including, but not limited to,arabinose, 2-fluoroarabinose, xylulose, and hexose.

In yet another embodiment, the antisense oligonucleotide comprises atleast one modified phosphate backbone selected from the group including,but not limited to, a phosphorothioate, a phosphorodithioate, aphosphoramidothioate, a phosphoramidate, a phosphordiamidate, amethylphosphonate, an alkyl phosphotriester, and a formacetal or analogthereof.

In yet another embodiment, the antisense oligonucleotide is ana-anomeric oligonucleotide. An a-anomeric oligonucleotide forms specificdouble-stranded hybrids with complementary RNA in which, contrary to theusual b-units, the strands run parallel to each other (Gautier et al.,1987, Nucl. Acids Res. 15:6625641). The oligonucleotide is a2′-0-methylribonucleotide (Inoue et al., 1987, Nucl. Acids Res.15:6131-6148), or a chimeric RNA-DNA analogue (Inoue et al., 1987, FEBSLett. 215:327-330).

Polynucleotides of the invention may be synthesized by standard methodsknown in the art, e.g. by use of an automated DNA synthesizer (such asare commercially available from Biosearch, Applied Biosystems, etc.). Asexamples, phosphorothioate oligonucleotides may be synthesized by themethod of Stein et al. (1988, Nucl. Acids Res. 16:3209),methylphosphonate oligonucleotides can be prepared by use of controlledpore glass polymer supports (Sarin et al., 1988, Proc. Natl. Acad. Sci.U.S.A. 85:7448-7451), etc.

While antisense nucleotides complementary to the coding region sequencecould be used, those complementary to the transcribed untranslatedregion are most preferred.

Potential antagonists according to the invention also include catalyticRNA, or a ribozyme (See, e.g., PCT International Publication WO90/11364, published Oct. 4, 1990; Sarver et al, Science 247:1222-1225(1990). While ribozymes that cleave mRNA at site specific recognitionsequences can be used to destroy mRNAs, the use of hammerhead ribozymesis preferred. Hammerhead ribozymes cleave mRNAs at locations dictated byflanking regions that form complementary base pairs with the targetmRNA. The sole requirement is that the target mRNA have the followingsequence of two bases: 5′-UG-3′. The construction and production ofhammerhead ribozymes is well known in the art and is described morefully in Haseloff and Gerlach, Nature 334:585-591 (1988). There arenumerous potential hammerhead ribozyme cleavage sites within thenucleotide sequence of SEQ ID NO:X. Preferably, the ribozyme isengineered so that the cleavage recognition site is located near the 5′end of the mRNA; i.e., to increase efficiency and minimize theintracellular accumulation of non-functional in RNA transcripts.

As in the antisense approach, the ribozymes of the invention can becomposed of modified oligonucleotides (e.g., for improved stability,targeting, etc.) and should be delivered to cells which express in vivo.DNA constructs encoding the ribozyme may be introduced into the cell inthe same manner as described above for the introduction of antisenseencoding DNA. A preferred method of delivery involves using a DNAconstruct “encoding” the ribozyme under the control of a strongconstitutive promoter, such as, for example, pol m or pol II promoter,so that transfected cells will produce sufficient quantities of theribozyme to destroy endogenous messages and inhibit translation. Sinceribozymes unlike antisense molecules, are catalytic, a lowerintracellular concentration is required for efficiency.

Antagonist/agonist compounds may be employed to inhibit the cell growthand proliferation effects of the polypeptides of the present inventionon neoplastic cells and tissues, i.e. stimulation of angiogenesis oftumors, and, therefore, retard or prevent abnormal cellular growth andproliferation, for example, in tumor formation or growth.

The antagonistlagonist may also be employed to prevent hyper-vasculardiseases, and prevent the proliferation of epithelial lens cells afterextracapsular cataract surgery. Prevention of the mitogenic activity ofthe polypeptides of the present invention may also be desirous in casessuch as restenosis after balloon angioplasty.

The antagonist/agonist may also be employed to prevent the growth ofscar tissue during wound healing.

The antagonist/agonist may also be employed to treat the diseasesdescribed herein.

Thus, the invention provides a method of treating disorders or diseases,including but not limited to the disorders or diseases listed throughoutthis application, associated with overexpression of a polynucleotide ofthe present invention by administering to a patient (a) an antisensemolecule directed to the polynucleotide of the present invention, and/or(b) a ribozyme directed to the polynucleotide of the present invention.

Binding Peptides and Other Molecules

The invention also encompasses screening methods for identifyingpolypeptides and nonpolypeptides that bind polypeptides of theinvention, and the binding molecules identified thereby. These bindingmolecules are useful, for example, as agonists and antagonists of thepolypeptides of the invention. Such agonists and antagonists can beused, in accordance with the invention, in the therapeutic embodimentsdescribed in detail, below.

This method comprises the steps of:

-   -   a. contacting polypeptides of the invention with a plurality of        molecules; and    -   b. identifying a molecule that binds the polypeptides of the        invention.

The step of contacting the polypeptides of the invention with theplurality of molecules may be effected in a number of ways. For example,one may contemplate immobilizing the polypeptides on a solid support andbringing a solution of the plurality of molecules in contact with theimmobilized polypeptides. Such a procedure would be akin to an affinitychromatographic process, with the affinity matrix being comprised of theimmobilized polypeptides of the invention. The molecules having aselective affinity for the polypeptides can then be purified by affinityselection. The nature of the solid support, process for attachment ofthe polypeptides to the solid support, solvent, and conditions of theaffinity isolation or selection are largely conventional and well knownto those of ordinary skill in the art.

Alternatively, one may also separate a plurality of polypeptides intosubstantially separate fractions comprising a subset of or individualpolypeptides. For instance, one can separate the plurality ofpolypeptides by gel electrophoresis, column chromatography, or likemethod known to those of ordinary skill for the separation ofpolypeptides. The individual polypeptides can also be produced by atransformed host cell in such a way as to be expressed on or about itsouter surface (e.g., a recombinant phage). Individual isolates can thenbe “probed” by the polypeptides of the invention, optionally in thepresence of an inducer should one be required for expression, todetermine if any selective affinity interaction takes place between thepolypeptides and the individual clone. Prior to contacting thepolypeptides with each fraction comprising individual polypeptides, thepolypeptides could first be transferred to a solid support foradditional convenience. Such a solid support may simply be a piece offilter membrane, such as one made of nitrocellulose or nylon. In thismanner, positive clones could be identified from a collection oftransformed host cells of an expression library, which harbor a DNAconstruct encoding a polypeptide having a selective affinity forpolypeptides of the invention. Furthermore, the amino acid sequence ofthe polypeptide having a selective affinity for the polypeptides of theinvention can be determined directly by conventional means or the codingsequence of the DNA encoding the polypeptide can frequently bedetermined more conveniently. The primary sequence can then be deducedfrom the corresponding DNA sequence. If the amino acid sequence is to bedetermined from the polypeptide itself, one may use microsequencingtechniques. The sequencing technique may include mass spectroscopy.

In certain situations, it may be desirable to wash away any unboundpolypeptides from a mixture of the polypeptides of the invention and theplurality of polypeptides prior to attempting to determine or to detectthe presence of a selective affinity interaction. Such a wash step maybe particularly desirable when the polypeptides of the invention or theplurality of polypeptides are bound to a solid support.

The plurality of molecules provided according to this method may beprovided by way of diversity libraries, such as random or combinatorialpeptide or nonpeptide libraries which can be screened for molecules thatspecifically bind polypeptides of the invention. Many libraries areknown in the art that can be used, e.g., chemically synthesizedlibraries, recombinant (e.g., phage display libraries), and in vitrotranslation-based libraries. Examples of chemically synthesizedlibraries are described in Fodor et al., 1991, Science 251:767-773;Houghten et al., 1991, Nature 354:84-86; Lam et al., 1991, Nature354:82-84; Medynski, 1994, Bio/Technology 12:709-710;Gallop et al.,1994, J. Medicinal Chemistry 37(9):1233-1251; Ohlmeyer et al., 1993,Proc. Natl. Acad. Sci. USA 90:10922-10926; Erb et al., 1994, Proc. Natl.Acad. Sci. USA 91:11422-11426; Houghten et al., 1992, Biotechniques13:412; Jayawickreme et al., 1994, Proc. Natl. Acad. Sci. USA91:1614-1618; Salmon et al., 1993, Proc. Natl. Acad. Sci. USA90:11708-11712; PCT Publication No. WO 93/20242; and Brenner and Lerner,1992, Proc. Natl. Acad. Sci. USA 89:5381-5383.

Examples of phage display libraries are described in Scott and Smith,1990, Science 249:386-390; Devlin et al., 1990, Science, 249:404-406;Christian, R. B., et al., 1992, J. Mol. Biol. 227:711-718); Lenstra,1992, J. Immunol. Meth. 152:149-157; Kay et al., 1993, Gene 128:59-65;and PCT Publication No. WO 94/18318 dated Aug. 18, 1994.

In vitro translation-based libraries include but are not limited tothose described in PCT Publication No. WO 91/05058 dated Apr. 18, 1991;and Mattheakis et al., 1994, Proc. Natl. Acad. Sci. USA 91:9022-9026.

By way of examples of nonpeptide libraries, a benzodiazepine library(see e.g., Bunin et al., 1994, Proc. Natl. Acad. Sci. USA 91:4708-4712)can be adapted for use. Peptoid libraries (Simon et al., 1992, Proc.Natl. Acad. Sci. USA 89:9367-9371) can also be used. Another example ofa library that can be used, in which the amide functionalities inpeptides have been permethylated to generate a chemically transformedcombinatorial library, is described by Ostresh et al. (1994, Proc. Natl.Acad. Sci. USA 91:11138-11142).

The variety of non-peptide libraries that are useful in the presentinvention is great. For example, Ecker and Crooke, 1995, Bio/Technology13:351-360 list benzodiazepines, hydantoins, piperazinediones,biphenyls, sugar analogs, beta-mercaptoketones, arylacetic acids,acylpiperidines, benzopyrans, cubanes, xanthines, aminimides, andoxazolones as among the chemical species that form the basis of variouslibraries.

Non-peptide libraries can be classified broadly into two types:decorated monomers and oligomers. Decorated monomer libraries employ arelatively simple scaffold structure upon which a variety functionalgroups is added. Often the scaffold will be a molecule with a knownuseful pharmacological activity. For example, the scaffold might be thebenzodiazepine structure.

Non-peptide oligomer libraries utilize a large number of monomers thatare assembled together in ways that create new shapes that depend on theorder of the monomers. Among the monomer units that have been used arecarbamates, pyrrolinones, and morpholinos. Peptoids, peptide-likeoligomers in which the side chain is attached to the alpha amino grouprather than the alpha carbon, form the basis of another version ofnon-peptide oligomer libraries. The first non-peptide oligomer librariesutilized a single type of monomer and thus contained a repeatingbackbone. Recent libraries have utilized more than one monomer, givingthe libraries added flexibility.

Screening the libraries can be accomplished by any of a variety ofcommonly known methods. See, e.g., the following references, whichdisclose screening of peptide libraries: Parmley and Smith, 1989, Adv.Exp. Med. Biol. 251:215-218; Scott and Smith, 1990, Science 249:386-390;Fowlkes et al., 1992; BioTechniques 13:422-427; Oldenburg et al., 1992,Proc. Natl. Acad. Sci. USA 89:5393-5397; Yu et al., 1994, Cell76:933-945; Staudt et al., 1988, Science 241:577-580; Bock et al., 1992,Nature 355:564-566; Tuerk et al., 1992, Proc. Natl. Acad. Sci. USA89:6988-6992; Ellington et al., 1992, Nature 355:850-852; U.S. Pat. No.5,096,815, U.S. Pat. No. 5,223,409, and U.S. Pat. No. 5,198,346, all toLadner et al.; Rebar and Pabo, 1993, Science 263:671-673; and CTPublication No. WO 94/18318.

In a specific embodiment, screening to identify a molecule that bindspolypeptides of the invention can be carried out by contacting thelibrary members with polypeptides of the invention immobilized on asolid phase and harvesting those library members that bind to thepolypeptides of the invention. Examples of such screening methods,termed “panning” techniques are described by way of example in Parmleyand Smith, 1988, Gene 73:305-318; Fowlkes et al., 1992, BioTecbniques13:422-427; PCT Publication No. WO 94/18318; and in references citedherein.

In another embodiment, the two-hybrid system for selecting interactingproteins in yeast (Fields and Song, 1989, Nature 340:245-246; Chien etal., 1991, Proc. Natl. Acad. Sci. USA 88:9578-9582) can be used toidentify molecules that specifically bind to polypeptides of theinvention.

Where the binding molecule is a polypeptide, the polypeptide can beconveniently selected from any peptide library, including random peptidelibraries, combinatorial peptide libraries, or biased peptide libraries.The term “biased” is used herein to mean that the method of generatingthe library is manipulated so as to restrict one or more parameters thatgovern the diversity of the resulting collection of molecules, in thiscase peptides.

Thus, a truly random peptide library would generate a collection ofpeptides in which the probability of finding a particular amino acid ata given position of the peptide is the same for all 20 amino acids. Abias can be introduced into the library, however, by specifying, forexample, that a lysine occur every fifth amino acid or that positions 4,8, and 9 of a decapeptide library be fixed to include only arginine.Clearly, many types of biases can be contemplated, and the presentinvention is not restricted to any particular bias. Furthermore, thepresent invention contemplates specific types of peptide libraries, suchas phage displayed peptide libraries and those that utilize a DNAconstruct comprising a lambda phage vector with a DNA insert.

As mentioned above, in the case of a binding molecule that is apolypeptide, the polypeptide may have about 6 to less than about 60amino acid residues, preferably about 6 to about 10 amino acid residues,and most preferably, about 6 to about 22 amino acids. In anotherembodiment, a binding polypeptide has in the range of 15-100 aminoacids, or 20-50 amino acids.

The selected binding polypeptide can be obtained by chemical synthesisor recombinant expression.

Other Activities

A polypeptide, polynucleotide, agonist, or antagonist of the presentinvention, as a result of the ability to stimulate vascular endothelialcell growth, may be employed in treatment for stimulatingre-vascularization of ischemic tissues due to various disease conditionssuch as thrombosis, arteriosclerosis, and other cardiovascularconditions. The polypeptide, polynucleotide, agonist, or antagonist ofthe present invention may also be employed to stimulate angiogenesis andlimb regeneration, as discussed above.

A polypeptide, polynucleotide, agonist, or antagonist of the presentinvention may also be employed for treating wounds due to injuries,burns, post-operative tissue repair, and ulcers since they are mitogenicto various cells of different origins, such as fibroblast cells andskeletal muscle cells, and therefore, facilitate the repair orreplacement of damaged or diseased tissue.

A polypeptide, polynucleotide, agonist, or antagonist of the presentinvention may also be employed stimulate neuronal growth and to treatand prevent neuronal damage which occurs in certain neuronal disordersor neuro-degenerative conditions such as Alzheimer's disease,Parkinson's disease, and AIDS-related complex. A polypeptide,polynucleotide, agonist, or antagonist of the present invention may havethe ability to stimulate chondrocyte growth, therefore, they may beemployed to enhance bone and periodontal regeneration and aid in tissuetransplants or bone grafts.

A polypeptide, polynucleotide, agonist, or antagonist of the presentinvention may be also be employed to prevent skin aging due to sunburnby stimulating keratinocyte growth.

A polypeptide, polynucleotide, agonist, or antagonist of the presentinvention may also be employed for preventing hair loss, since FGFfamily members activate hair-forming cells and promotes melanocytegrowth. Along the same lines, a polypeptide, polynucleotide, agonist, orantagonist of the present invention may be employed to stimulate growthand differentiation of hematopoietic cells and bone marrow cells whenused in combination with other cytokines.

A polypeptide, polynucleotide, agonist, or antagonist of the presentinvention may also be employed to maintain organs before transplantationor for supporting cell culture of primary tissues. A polypeptide,polynucleotide, agonist, or antagonist of the present invention may alsobe employed for inducing tissue of mesodermal origin to differentiate inearly embryos.

A polypeptide, polynucleotide, agonist, or antagonist of the presentinvention may also increase or decrease the differentiation orproliferation of embryonic stem cells, besides, as discussed above,hematopoietic lineage.

A polypeptide, polynucleotide, agonist, or antagonist of the presentinvention may also be used to modulate mammalian characteristics, suchas body height, weight, hair color, eye color, skin, percentage ofadipose tissue, pigmentation, size, and shape (e.g., cosmetic surgery).Similarly, a polypeptide, polynucleotide, agonist, or antagonist of thepresent invention may be used to modulate mammalian metabolism affectingcatabolism, anabolism, processing, utilization, and storage of energy.

A polypeptide, polynucleotide, agonist, or antagonist of the presentinvention may be used to change a mammal's mental state or physicalstate by influencing biorhythms, caricadic rhythms, depression(including depressive disorders), tendency for violence, tolerance forpain, reproductive capabilities (preferably by Activin or Inhibin-likeactivity), hormonal or endocrine levels, appetite, libido, memory,stress, or other cognitive qualities.

A polypeptide, polynucleotide, agonist, or antagonist of the presentinvention may also be used as a food additive or preservative, such asto increase or decrease storage capabilities, fat content, lipid,protein, carbohydrate, vitamins, minerals, cofactors or othernutritional components.

The above-recited applications have uses in a wide variety of hosts.Such hosts include, but are not limited to, human, murine, rabbit, goat,guinea pig, camel, horse, mouse, rat, hamster, pig, micro-pig, chicken,goat, cow, sheep, dog, cat, non-human primate, and human. In specificembodiments, the host is a mouse, rabbit, goat, guinea pig, chicken,rat, hamster, pig, sheep, dog or cat. In preferred embodiments, the hostis a mammal. In most preferred embodiments, the host is a human.

Other Preferred Embodiments

Other preferred embodiments of the claimed invention include an isolatednucleic acid molecule comprising a nucleotide sequence which is at least95% identical to a sequence of at least about 50 contiguous nucleotidesin the nucleotide sequence of SEQ ID NO:X or the complementary strandthereto, the nucleotide sequence as defined in column 5 of Table 1B.1 orcolumns 8 and 9 of Table 2 or the complementary strand thereto, and/orcDNA contained in ATCC Deposit No:Z.

Also preferred is a nucleic acid molecule wherein said sequence ofcontiguous nucleotides is included in the nucleotide sequence of theportion of SEQ ID NO:X as defined in column 5, “ORF (From-To)”, in Table1B.1.

Also preferred is a nucleic acid molecule wherein said sequence ofcontiguous nucleotides is included in the nucleotide sequence of theportion of SEQ ID NO:X as defined in columns 8 and 9, “NT From” and “NTTo” respectively, in Table 2.

Also preferred is an isolated nucleic acid molecule comprising anucleotide sequence which is at least 95% identical to a sequence of atleast about 150 contiguous nucleotides in the nucleotide sequence of SEQID NO:X or the complementary strand thereto, the nucleotide sequence asdefined in column 5 of Table 1B.1 or columns 8 and 9 of Table 2 or thecomplementary strand thereto, and/or cDNA contained in ATCC DepositNo:Z.

Further preferred is an isolated nucleic acid molecule comprising anucleotide sequence which is at least 95% identical to a sequence of atleast about 500 contiguous nucleotides in the nucleotide sequence of SEQID NO:X or the complementary strand thereto, the nucleotide sequence asdefined in column 5 of Table 1B.1 or columns 8 and 9 of Table 2 or thecomplementary strand thereto, and/or cDNA contained in ATCC DepositNo:Z.

A further preferred embodiment is a nucleic acid molecule comprising anucleotide sequence which is at least 95% identical to the nucleotidesequence of the portion of SEQ ID NO:X defined in column 5, “ORF(From-To)”, in Table 1B.1.

A further preferred embodiment is a nucleic acid molecule comprising anucleotide sequence which is at least 95% identical to the nucleotidesequence of the portion of SEQ ID NO:X defined in columns 8 and 9, “NTFrom” and “NT To”, respectively, in Table 2.

A further preferred embodiment is an isolated nucleic acid moleculecomprising a nucleotide sequence which is at least 95% identical to thecomplete nucleotide sequence of SEQ ID NO:X or the complementary strandthereto, the nucleotide sequence as defined in column 5 of Table 1B.1 orcolumns 8 and 9 of Table 2 or the complementary strand thereto, and/orcDNA contained in ATCC Deposit No:Z.

Also preferred is an isolated nucleic acid molecule which hybridizesunder stringent hybridization conditions to a nucleic acid moleculecomprising a nucleotide sequence of SEQ ID NO:X or the complementarystrand thereto, the nucleotide sequence as defined in column 5 of Table1B.1 or columns 8 and 9 of Table 2 or the complementary strand thereto,and/or cDNA contained in ATCC Deposit No:Z, wherein said nucleic acidmolecule which hybridizes does not hybridize under stringenthybridization conditions to a nucleic acid molecule having a nucleotidesequence consisting of only A residues or of only T residues.

Also preferred is a composition of matter comprising a DNA moleculewhich comprises the cDNA contained in ATCC Deposit No:Z.

Also preferred is an isolated nucleic acid molecule comprising anucleotide sequence which is at least 95% identical to a sequence of atleast 50 contiguous nucleotides of the cDNA sequence contained in ATCCDeposit No:Z.

Also preferred is an isolated nucleic acid molecule, wherein saidsequence of at least 50 contiguous nucleotides is included in thenucleotide sequence of an open reading frame sequence encoded by cDNAcontained in ATCC Deposit No:Z.

Also preferred is an isolated nucleic acid molecule comprising anucleotide sequence which is at least 95% identical to sequence of atleast 150 contiguous nucleotides in the nucleotide sequence encoded bycDNA contained in ATCC Deposit No:Z.

A further preferred embodiment is an isolated nucleic acid moleculecomprising a nucleotide sequence which is at least 95% identical tosequence of at least 500 contiguous nucleotides in the nucleotidesequence encoded by cDNA contained in ATCC Deposit No:Z.

A further preferred embodiment is an isolated nucleic acid moleculecomprising a nucleotide sequence which is at least 95% identical to thecomplete nucleotide sequence encoded by cDNA contained in ATCC DepositNo:Z.

A further preferred embodiment is a method for detecting in a biologicalsample a nucleic acid molecule comprising a nucleotide sequence which isat least 95% identical to a sequence of at least 50 contiguousnucleotides in a sequence selected from the group consisting of: anucleotide sequence of SEQ ID NO:X or the complementary strand thereto;the nucleotide sequence as defined in column 5 of Table 1B.1 or columns8 and 9 of Table 2 or the complementary strand thereto; and a nucleotidesequence encoded by cDNA contained in ATCC Deposit No:Z; which methodcomprises a step of comparing a nucleotide sequence of at least onenucleic acid molecule in said sample with a sequence selected from saidgroup and determining whether the sequence of said nucleic acid moleculein said sample is at least 95% identical to said selected sequence.

Also preferred is the above method wherein said step of comparingsequences comprises determining the extent of nucleic acid hybridizationbetween nucleic acid molecules in said sample and a nucleic acidmolecule comprising said sequence selected from said group. Similarly,also preferred is the above method wherein said step of comparingsequences is performed by comparing the nucleotide sequence determinedfrom a nucleic acid molecule in said sample with said sequence selectedfrom said group. The nucleic acid molecules can comprise DNA moleculesor RNA molecules.

A further preferred embodiment is a method for identifying the species,tissue or cell type of a biological sample which method comprises a stepof detecting nucleic acid molecules in said sample, if any, comprising anucleotide sequence that is at least 95% identical to a sequence of atleast 50 contiguous nucleotides in a sequence selected from the groupconsisting of: a nucleotide sequence of SEQ ID NO:X or the complementarystrand thereto; the nucleotide sequence as defined in column 5 of Table1B.1 or columns 8 and 9 of Table 2 or the complementary strand thereto;and a nucleotide sequence of the cDNA contained in ATCC Deposit No:Z.

The method for identifying the species, tissue or cell type of abiological sample can comprise a step of detecting nucleic acidmolecules comprising a nucleotide sequence in a panel of at least twonucleotide sequences, wherein at least one sequence in said panel is atleast 95% identical to a sequence of at least 50 contiguous nucleotidesin a sequence selected from said group.

Also preferred is a method for diagnosing in a subject a pathologicalcondition associated with abnormal structure or expression of anucleotide sequence of SEQ ID NO:X or the complementary strand thereto;the nucleotide sequence as defined in column 5 of Table 1B.1 or columns8 and 9 of Table 2 or the complementary strand thereto; or the cDNAcontained in ATCC Deposit No:Z which encodes a protein, wherein themethod comprises a step of detecting in a biological sample obtainedfrom said subject nucleic acid molecules, if any, comprising anucleotide sequence that is at least 95% identical to a sequence of atleast 50 contiguous nucleotides in a sequence selected from the groupconsisting of: a nucleotide sequence of SEQ ID NO:X or the complementarystrand thereto; the nucleotide sequence as defined in column 5 of Table1B.1 or columns 8 and 9 of Table 2 or the complementary strand thereto;and a nucleotide sequence of cDNA contained in ATCC Deposit No:Z.

The method for diagnosing a pathological condition can comprise a stepof detecting nucleic acid molecules comprising a nucleotide sequence ina panel of at least two nucleotide sequences, wherein at least onesequence in said panel is at least 95% identical to a sequence of atleast 50 contiguous nucleotides in a sequence selected from said group.

Also preferred is a composition of matter comprising isolated nucleicacid molecules wherein the nucleotide sequences of said nucleic acidmolecules comprise a panel of at least two nucleotide sequences, whereinat least one sequence in said panel is at least 95% identical to asequence of at least 50 contiguous nucleotides in a sequence selectedfrom the group consisting of: a nucleotide sequence of SEQ ID NO:X orthe complementary strand thereto; the nucleotide sequence as defined incolumn 5 of Table 1B.1 or columns 8 and 9 of Table 2 or thecomplementary strand thereto; and a nucleotide sequence encoded by cDNAcontained in ATCC Deposit No:Z. The nucleic acid molecules can compriseDNA molecules or RNA molecules.

Also preferred is a composition of matter comprising isolated nucleicacid molecules wherein the nucleotide sequences of said nucleic acidmolecules comprise a DNA microarray or “chip” of at least 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 100, 150, 200, 250, 300, 500,1000, 2000, 3000, or 4000 nucleotide sequences, wherein at least onesequence in said DNA microarray or “chip” is at least 95% identical to asequence of at least 50 contiguous nucleotides in a sequence selectedfrom the group consisting of: a nucleotide sequence of SEQ ID NO:Xwherein X is any integer as defined in Table 1A and/or Table 1B.1; and anucleotide sequence encoded by a human cDNA clone identified by a cDNA“Clone ID” in Table 1A and/or Table 1B.1.

Also preferred is an isolated polypeptide comprising an amino acidsequence at least 90% identical to a sequence of at least about 10contiguous amino acids in the polypeptide sequence of SEQ ID NO:Y; apolypeptide encoded by SEQ ID NO:X or the complementary strand thereto;the polypeptide encoded by the nucleotide sequence as defined in columns8 and 9 of Table 2; and/or a polypeptide encoded by cDNA contained inATCC Deposit No:Z.

Also preferred is an isolated polypeptide comprising an amino acidsequence at least 95% identical to a sequence of at least about 30contiguous amino acids in the amino acid sequence of SEQ ID NO:Y; apolypeptide encoded by SEQ ID NO:X or the complementary strand thereto;the polypeptide encoded by the nucleotide sequence as defined in columns8 and 9 of Table 2; and/or a polypeptide encoded by cDNA contained inATCC Deposit No:Z.

Further preferred is an isolated polypeptide comprising an amino acidsequence at least 95% identical to a sequence of at least about 100contiguous amino acids in the amino acid sequence of SEQ ID NO:Y; apolypeptide encoded by SEQ ID NO:X or the complementary strand thereto;the polypeptide encoded by the nucleotide sequence as defined in columns8 and 9 of Table 2; and/or a polypeptide encoded by cDNA contained inATCC Deposit No:Z.

Further preferred is an isolated polypeptide comprising an amino acidsequence at least 95% identical to the complete amino acid sequence ofSEQ ID NO:Y; a polypeptide encoded by SEQ ID NO:X or the complementarystrand thereto; the polypeptide encoded by the nucleotide sequence asdefined in columns 8 and 9 of Table 2; and/or a polypeptide encoded bycDNA contained in ATCC Deposit No:Z.

Further preferred is an isolated polypeptide comprising an amino acidsequence at least 90% identical to a sequence of at least about 10contiguous amino acids in the complete amino acid sequence of apolypeptide encoded by contained in ATCC Deposit No:Z.

Also preferred is a polypeptide wherein said sequence of contiguousamino acids is included in the amino acid sequence of a portion of saidpolypeptide encoded by cDNA contained in ATCC Deposit No:Z; apolypeptide encoded by SEQ ID NO:X or the complementary strand thereto;the polypeptide encoded by the nucleotide sequence as defined in columns8 and 9 of Table 2; and/or the polypeptide sequence of SEQ ID NO:Y.

Also preferred is an isolated polypeptide comprising an amino acidsequence at least 95% identical to a sequence of at least about 30contiguous amino acids in the amino acid sequence of a polypeptideencoded by the cDNA contained in ATCC Deposit No:Z.

Also preferred is an isolated polypeptide comprising an amino acidsequence at least 95% identical to a sequence of at least about 100contiguous amino acids in the amino acid sequence of a polypeptideencoded by cDNA contained in ATCC Deposit No:Z.

Also preferred is an isolated polypeptide comprising an amino acidsequence at least 95% identical to the amino acid sequence of apolypeptide encoded by the cDNA contained in ATCC Deposit No:Z.

Further preferred is an isolated antibody which binds specifically to apolypeptide comprising an amino acid sequence that is at least 90%identical to a sequence of at least 10 contiguous amino acids in asequence selected from the group consisting of: a polypeptide sequenceof SEQ ID NO:Y; a polypeptide encoded by SEQ ID NO:X or thecomplementary strand thereto; the polypeptide encoded by the nucleotidesequence as defined in columns 8 and 9 of Table 2; and a polypeptideencoded by the cDNA contained in ATCC Deposit No:Z.

Further preferred is a method for detecting in a biological sample apolypeptide comprising an amino acid sequence which is at least 90%identical to a sequence of at least 10 contiguous amino acids in asequence selected from the group consisting of: a polypeptide sequenceof SEQ ID NO:Y; a polypeptide encoded by SEQ ID NO:X or thecomplementary strand thereto; the polypeptide encoded by the nucleotidesequence as defined in columns 8 and 9 of Table 2; and a polypeptideencoded by the cDNA contained in ATCC Deposit No:Z; which methodcomprises a step of comparing an amino acid sequence of at least onepolypeptide molecule in said sample with a sequence selected from saidgroup and determining whether the sequence of said polypeptide moleculein said sample is at least 90% identical to said sequence of at least 10contiguous amino acids.

Also preferred is the above method wherein said step of comparing anamino acid sequence of at least one polypeptide molecule in said samplewith a sequence selected from said group comprises determining theextent of specific binding of polypeptides in said sample to an antibodywhich binds specifically to a polypeptide comprising an amino acidsequence that is at least 90% identical to a sequence of at least 10contiguous amino acids in a sequence selected from the group consistingof: a polypeptide sequence of SEQ ID NO:Y; a polypeptide encoded by SEQID NO:X or the complementary strand thereto; the polypeptide encoded bythe nucleotide sequence as defined in columns 8 and 9 of Table 2; and apolypeptide encoded by the cDNA contained in ATCC Deposit No:Z.

Also preferred is the above method wherein said step of comparingsequences is performed by comparing the amino acid sequence determinedfrom a polypeptide molecule in said sample with said sequence selectedfrom said group.

Also preferred is a method for identifying the species, tissue or celltype of a biological sample which method comprises a step of detectingpolypeptide molecules in said sample, if any, comprising an amino acidsequence that is at least 90% identical to a sequence of at least 10contiguous amino acids in a sequence selected from the group consistingof: polypeptide sequence of SEQ ID NO:Y; a polypeptide encoded by SEQ IDNO:X or the complementary strand thereto; the polypeptide encoded by thenucleotide sequence as defined in columns 8 and 9 of Table 2; and apolypeptide encoded by the cDNA contained in ATCC Deposit No:Z.

Also preferred is the above method for identifying the species, tissueor cell type of a biological sample, which method comprises a step ofdetecting polypeptide molecules comprising an amino acid sequence in apanel of at least two amino acid sequences, wherein at least onesequence in said panel is at least 90% identical to a sequence of atleast 10 contiguous amino acids in a sequence selected from the abovegroup.

Also preferred is a method for diagnosing in a subject a pathologicalcondition associated with abnormal structure or expression of a nucleicacid sequence identified in Table 1A, 1B or Table 2 encoding apolypeptide, which method comprises a step of detecting in a biologicalsample obtained from said subject polypeptide molecules comprising anamino acid sequence in a panel of at least two amino acid sequences,wherein at least one sequence in said panel is at least 90% identical toa sequence of at least 10 contiguous amino acids in a sequence selectedfrom the group consisting of: polypeptide sequence of SEQ ID NO:Y; apolypeptide encoded by SEQ ID NO:X or the complementary strand thereto;the polypeptide encoded by the nucleotide sequence as defined in columns8 and 9 of Table 2; and a polypeptide encoded by the cDNA contained inATCC Deposit No:Z.

In any of these methods, the step of detecting said polypeptidemolecules includes using an antibody.

Also preferred is an isolated nucleic acid molecule comprising anucleotide sequence which is at least 95% identical to a nucleotidesequence encoding a polypeptide wherein said polypeptide comprises anamino acid sequence that is at least 90% identical to a sequence of atleast 10 contiguous amino acids in a sequence selected from the groupconsisting of: polypeptide sequence of SEQ ID NO:Y; a polypeptideencoded by SEQ ID NO:X or the complementary strand thereto; thepolypeptide encoded by the nucleotide sequence as defined in columns 8and 9 of Table 2; and a polypeptide encoded by the cDNA contained inATCC Deposit No:Z.

Also preferred is an isolated nucleic acid molecule, wherein saidnucleotide sequence encoding a polypeptide has been optimized forexpression of said polypeptide in a prokaryotic host.

Also preferred is a polypeptide molecule, wherein said polypeptidecomprises an amino acid sequence selected from the group consisting of:polypeptide sequence of SEQ ID NO:Y; a polypeptide encoded by SEQ IDNO:X or the complementary strand thereto; the polypeptide encoded by thenucleotide sequence as defined in columns 8 and 9 of Table 2; and apolypeptide encoded by the cDNA contained in ATCC Deposit No:Z.

Further preferred is a method of making a recombinant vector comprisinginserting any of the above isolated nucleic acid molecule into a vector.Also preferred is the recombinant vector produced by this method. Alsopreferred is a method of making a recombinant host cell comprisingintroducing the vector into a host cell, as well as the recombinant hostcell produced by this method.

Also preferred is a method of making an isolated polypeptide comprisingculturing this recombinant host cell under conditions such that saidpolypeptide is expressed and recovering said polypeptide. Also preferredis this method of making an isolated polypeptide, wherein saidrecombinant host cell is a eukaryotic cell and said polypeptide is ahuman protein comprising an amino acid sequence selected from the groupconsisting of: polypeptide sequence of SEQ ID NO:Y; a polypeptideencoded by SEQ ID NO:X or the complementary strand thereto; thepolypeptide encoded by the nucleotide sequence as defined in columns 8and 9 of Table 2; and a polypeptide encoded by the cDNA contained inATCC Deposit No:Z. The isolated polypeptide produced by this method isalso preferred.

Also preferred is a method of treatment of an individual in need of anincreased level of a protein activity, which method comprisesadministering to such an individual a Therapeutic comprising an amountof an isolated polypeptide, polynucleotide, immunogenic fragment oranalogue thereof, binding agent, antibody, or antigen binding fragmentof the claimed invention effective to increase the level of said proteinactivity in said individual.

Also preferred is a method of treatment of an individual in need of adecreased level of a protein activity, which method comprisedadministering to such an individual a Therapeutic comprising an amountof an isolated polypeptide, polynucleotide, immunogenic fragment oranalogue thereof, binding agent, antibody, or antigen binding fragmentof the claimed invention effective to decrease the level of said proteinactivity in said individual.

Also preferred is a method of treatment of an individual in need of aspecific delivery of toxic compositions to diseased cells (e.g., tumors,leukemias or lymphomas), which method comprises administering to such anindividual a Therapeutic comprising an amount of an isolated polypeptideof the invention, including, but not limited to a binding agent, orantibody of the claimed invention that are associated with toxin orcytotoxic prodrugs.

Having generally described the invention, the same will be more readilyunderstood by reference to the following examples, which are provided byway of illustration and are not intended as limiting.

Description of Table 6

Table 6 summarizes some of the ATCC Deposits, Deposit dates, and ATCCdesignation numbers of deposits made with the ATCC in connection withthe present application. These deposits were made in addition to thosedescribed in the Table 1A. TABLE 6 ATCC Deposits Deposit Date ATCCDesignation Number LP01, LP02, LP03, LP04, May-20-97 209059, 209060,209061, LP05, LP06, LP07, LP08, 209062, 209063, 209064, LP09, LP10,LP11, 209065, 209066, 209067, 209068, 209069 LP12 Jan-12-98 209579 LP13Jan-12-98 209578 LP14 Jul-16-98 203067 LP15 Jul-16-98 203068 LP16Feb-1-99 203609 LP17 Feb-1-99 203610 LP20 Nov-17-98 203485 LP21Jun-18-99 PTA-252 LP22 Jun-18-99 PTA-253 LP23 Dec-22-99 PTA-1081

EXAMPLES Example 1 Isolation of a Selected cDNA Clone From the DepositedSample

Each ATCC Deposit No:Z is contained in a plasmid vector. Table 7identifies the vectors used to construct the cDNA library from whicheach clone was isolated. In many cases, the vector used to construct thelibrary is a phage vector from which a plasmid has been excised. Thefollowing correlates the related plasmid for each phage vector used inconstructing the cDNA library. For example, where a particular clone isidentified in Table 7 as being isolated in the vector “Lambda Zap,” thecorresponding deposited clone is in “pBluescript.” Vector Used toConstruct Library Corresponding Deposited Plasmid Lambda Zap pBluescript(pBS) Uni-Zap XR pBluescript (pBS) Zap Express pBK lafmid BA plafmid BApSport1 pSport1 pCMVSport 2.0 pCMVSport 2.0 pCMVSport 3.0 pCMVSport 3.0pCR ® 2.1 pCR ® 2.1

Vectors Lambda Zap (U.S. Pat. Nos. 5,128,256 and 5,286,636), Uni-Zap XR(U.S. Pat. Nos. 5,128,256 and 5,286,636), Zap Express (U.S. Pat. Nos.5,128,256 and 5,286,636), pBluescript (pBS) (Short, J. M. et al.,Nucleic Acids Res. 16:7583-7600 (1988); Alting-Mees, M. A. and Short, J.M., Nucleic Acids Res. 17:9494 (1989)) and pBK (Alting-Mees, M. A. etal., Strategies 5:58-61 (1992)) are commercially available fromStratagene Cloning Systems, Inc., 11011 N. Torrey Pines Road, La Jolla,Calif., 92037. pBS contains an ampicillin resistance gene and pBKcontains a neomycin resistance gene. Both can be transformed into E.coli strain XL-1 Blue, also available from Stratagene. pBS comes in 4forms SK+, SK−, KS+ and KS. The S and K refers to the orientation of thepolylinker to the T7 and T3 primer sequences which flank the polylinkerregion (“S” is for SacI and “K” is for KpnI which are the first sites oneach respective end of the linker). “+” or “−” refer to the orientationof the f1 origin of replication (“ori”), such that in one orientation,single stranded rescue initiated from the f1 ori generates sense strandDNA and in the other, antisense.

Vectors pSport1, pCMVSport 2.0 and pCMVSport 3.0, were obtained fromLife Technologies, Inc., P.O. Box 6009, Gaithersburg, Md. 20897. AllSport vectors contain an ampicillin resistance gene and may betransformed into E. coli strain DH10B, also available from LifeTechnologies. (See, for instance, Gruber, C. E., et al., Focus 15:59(1993)). Vector lafmid BA (Bento Soares, Columbia University, NY)contains an ampicillin resistance gene and can be transformed into E.coli strain XL-1 Blue. Vector pCR®2.1, which is available fromInvitrogen, 1600 Faraday Avenue, Carlsbad, Calif. 92008, contains anampicillin resistance gene and may be transformed into E. coli strainDH10B, available from Life Technologies. (See, for instance, Clark, J.M., Nuc. Acids Res. 16:9677-9686 (1988) and Mead, D. et al.,Bio/Technology 9: (1991)). Preferably, a polynucleotide of the presentinvention does not comprise the phage vector sequences identified forthe particular clone in Table 7, as well as the corresponding plasmidvector sequences designated above.

The deposited material in the sample assigned the ATCC Deposit Numbercited by reference to Table 1A, Table 2, Table 6 and Table 7 for anygiven cDNA clone also may contain one or more additional plasmids, eachcomprising a cDNA clone different from that given clone. Thus, depositssharing the same ATCC Deposit Number contain at least a plasmid for eachATCC Deposit No:Z. TABLE 7 ATCC Libraries owned by Catalog CatalogDescription Vector Deposit HUKA HUKB HUKC HUKD Human Uterine CancerLambda ZAP II LP01 HUKE HUKF HUKG HCNA HCNB Human Colon Lambda Zap IILP01 HFFA Human Fetal Brain, random Lambda Zap II LP01 primed HTWAResting T-Cell Lambda ZAP II LP01 HBQA Early Stage Human Brain, LambdaZAP II LP01 random primed HLMB HLMF HLMG HLMH breast lymph node CDNAlibrary Lambda ZAP II LP01 HLMI HLMJ HLMM HLMN HCQA HCQB human coloncancer Lamda ZAP II LP01 HMEA HMEC HMED HMEE Human Microvascular LambdaZAP II LP01 HMEF HMEG HMEI HMEJ Endothelial Cells, fract. A HMEK HMELHUSA HUSC Human Umbilical Vein Lambda ZAP II LP01 Endothelial Cells,fract. A HLQA HLQB Hepatocellular Tumor Lambda ZAP II LP01 HHGA HHGBHHGC HHGD Hemangiopericytoma Lambda ZAP II LP01 HSDM Human StriatumDepression, re- Lambda ZAP II LP01 rescue HUSH H Umbilical VeinEndothelial Lambda ZAP II LP01 Cells, frac A, re-excision HSGS Salivarygland, subtracted Lambda ZAP II LP01 HFXA HFXB HFXC HFXD Brain frontalcortex Lambda ZAP II LP01 HFXE HFXF HFXG HFXH HPQA HPQB HPQC PERM TF274Lambda ZAP II LP01 HFXJ HFXK Brain Frontal Cortex, re-excision LambdaZAP II LP01 HCWA HCWB HCWC HCWD CD34 positive cells (Cord Blood) ZAPExpress LP02 HCWE HCWF HCWG HCWH HCWI HCWJ HCWK HCUA HCUB HCUC CD34depleted Buffy Coat (Cord ZAP Express LP02 Blood) HRSM A-14 cell lineZAP Express LP02 HRSA A1-CELL LINE ZAP Express LP02 HCUD HCUE HCUF HCUGCD34 depleted Buffy Coat (Cord ZAP Express LP02 HCUH HCUI Blood),re-excision HBXE HBXF HBXG H. Whole Brain #2, re-excision ZAP ExpressLP02 HRLM L8 cell line ZAP Express LP02 HBXA HBXB HBXC HBXD Human WholeBrain #2 - Oligo ZAP Express LP02 dT > 1.5 Kb HUDA HUDB HUDC Testes ZAPExpress LP02 HHTM HHTN HHTO H. hypothalamus, frac A; re- ZAP ExpressLP02 excision HHTL H. hypothalamus, frac A ZAP Express LP02 HASA HASDHuman Adult Spleen Uni-ZAP XR LP03 HFKC HFKD HFKE HFKF Human FetalKidney Uni-ZAP XR LP03 HFKG HE8A HE8B HE8C HE8D Human 8 Week WholeEmbryo Uni-ZAP XR LP03 HE8E HE8F HE8M HE8N HGBA HGBD HGBE HGBF HumanGall Bladder Uni-ZAP XR LP03 HGBG HGBH HGBI HLHA HLHB HLHC HLHD HumanFetal Lung III Uni-ZAP XR LP03 HLHE HLHF HLHG HLHH HLHQ HPMA HPMB HPMCHPMD Human Placenta Uni-ZAP XR LP03 HPME HPMF HPMG HPMH HPRA HPRB HPRCHPRD Human Prostate Uni-ZAP XR LP03 HSIA HSIC HSID HSIE Human AdultSmall Intestine Uni-ZAP XR LP03 HTEA HTEB HTEC HTED Human Testes Uni-ZAPXR LP03 HTEE HTEF HTEG HTEH HTEI HTEJ HTEK HTPA HTPB HTPC HTPD HumanPancreas Tumor Uni-ZAP XR LP03 HTPE HTTA HTTB HTTC HTTD Human TestesTumor Uni-ZAP XR LP03 HTTE HTTF HAPA HAPB HAPC HAPM Human AdultPulmonary Uni-ZAP XR LP03 HETA HETB HETC HETD Human Endometrial TumorUni-ZAP XR LP03 HETE HETF HETG HETH HETI HHFB HHFC HHFD HHFE Human FetalHeart Uni-ZAP XR LP03 HHFF HHFG HHFH HHFI HHPB HHPC HHPD HHPE HumanHippocampus Uni-ZAP XR LP03 HHPF HHPG HHPH HCE1 HCE2 HCE3 HCE4 HumanCerebellum Uni-ZAP XR LP03 HCE5 HCEB HCEC HCED HCEE HCEF HCEG HUVB HUVCHUVD HUVE Human Umbilical Vein, Endo. Uni-ZAP XR LP03 remake HSTA HSTBHSTC HSTD Human Skin Tumor Uni-ZAP XR LP03 HTAA HTAB HTAC HTAD HumanActivated T-Cells Uni-ZAP XR LP03 HTAE HFEA HFEB HFEC Human FetalEpithelium (Skin) Uni-ZAP XR LP03 HJPA HJPB HJPC HJPD HUMAN JURKATUni-ZAP XR LP03 MEMBRANE BOUND POLYSOMES HESA Human epithelioid sarcomaUni-Zap XR LP03 HLTA HLTB HLTC HLTD Human T-Cell Lymphoma Uni-ZAP XRLP03 HLTE HLTF HFTA HFTB HFTC HFTD Human Fetal Dura Mater Uni-ZAP XRLP03 HRDA HRDB HRDC HRDD Human Rhabdomyosarcoma Uni-ZAP XR LP03 HRDEHRDF HCAA HCAB HCAC Cem cells cyclohexamide treated Uni-ZAP XR LP03 HRGAHRGB HRGC HRGD Raji Cells, cyclohexamide treated Uni-ZAP XR LP03 HSUAHSUB HSUC HSUM Supt Cells, cyclohexamide treated Uni-ZAP XR LP03 HT4AHT4C HT4D Activated T-Cells, 12 hrs. Uni-ZAP XR LP03 HE9A HE9B HE9C HE9DNine Week Old Early Stage Uni-ZAP XR LP03 HE9E HE9F HE9G HE9H Human HE9MHE9N HATA HATB HATC HATD Human Adrenal Gland Tumor Uni-ZAP XR LP03 HATEHT5A Activated T-Cells, 24 hrs. Uni-ZAP XR LP03 HFGA HFGM Human FetalBrain Uni-ZAP XR LP03 HNEA HNEB HNEC HNED Human Neutrophil Uni-ZAP XRLP03 HNEE HBGB HBGD Human Primary Breast Cancer Uni-ZAP XR LP03 HBNAHBNB Human Normal Breast Uni-ZAP XR LP03 HCAS Cem Cells, cyclohexamideUni-ZAP XR LP03 treated, subtra HHPS Human Hippocampus, subtracted pBSLP03 HKCS HKCU Human Colon Cancer, subtracted pBS LP03 HRGS Raji cells,cyclohexamide treated, pBS LP03 subtracted HSUT Supt cells,cyclohexamide treated, pBS LP03 differentially expressed HT4S ActivatedT-Cells, 12 hrs, Uni-ZAP XR LP03 subtracted HCDA HCDB HCDC HCDD HumanChondrosarcoma Uni-ZAP XR LP03 HCDE HOAA HOAB HOAC Human OsteosarcomaUni-ZAP XR LP03 HTLA HTLB HTLC HTLD Human adult testis, large insertsUni-ZAP XR LP03 HTLE HTLF HLMA HLMC HLMD Breast Lymph node cDNA libraryUni-ZAP XR LP03 H6EA H6EB H6EC HL-60, PMA 4 H Uni-ZAP XR LP03 HTXA HTXBHTXC HTXD Activated T-Cell Uni-ZAP XR LP03 HTXE HTXF HTXG HTXH (12hs)/Thiouridine labelledEco HNFA HNFB HNFC HNFD Human Neutrophil,Activated Uni-ZAP XR LP03 HNFE HNFF HNFG HNFH HNFJ HTOB HTOC HUMANTONSILS, FRACTION 2 Uni-ZAP XR LP03 HMGB Human OB MG63 control Uni-ZAPXR LP03 fraction I HOPB Human OB HOS control fraction I Uni-ZAP XR LP03HORB Human OB HOS treated (10 nM Uni-ZAP XR LP03 E2) fraction I HSVAHSVB HSVC Human Chronic Synovitis Uni-ZAP XR LP03 HROA HUMAN STOMACHUni-ZAP XR LP03 HBJA HBJB HBJC HBJD HUMAN B CELL LYMPHOMA Uni-ZAP XRLP03 HBJE HBJF HBJG HBJH HBJI HBJJ HBJK HCRA HCRB HCRC human corpuscolosum Uni-ZAP XR LP03 HODA HODB HODC HODD human ovarian cancer Uni-ZAPXR LP03 HDSA Dermatofibrosarcoma Uni-ZAP XR LP03 Protuberance HMWA HMWBHMWC Bone Marrow Cell Line (RS4; 11) Uni-ZAP XR LP03 HMWD HMWE HMWF HMWGHMWH HMWI HMWJ HSOA stomach cancer (human) Uni-ZAP XR LP03 HERA SKINUni-ZAP XR LP03 HMDA Brain-medulloblastoma Uni-ZAP XR LP03 HGLA HGLBHGLD Glioblastoma Uni-ZAP XR LP03 HEAA H. Atrophic Endometrium Uni-ZAPXR LP03 HBCA HBCB H. Lymph node breast Cancer Uni-ZAP XR LP03 HPWT HumanProstate BPH, re-excision Uni-ZAP XR LP03 HFVG HFVH HFVI Fetal Liver,subtraction II pBS LP03 HNFI Human Neutrophils, Activated, pBS LP03re-excision HBMB HBMC HBMD Human Bone Marrow, re-excision pBS LP03 HKMLHKMM HKMN H. Kidney Medulla, re-excision pBS LP03 HKIX HKIY H. KidneyCortex, subtracted pBS LP03 HADT H. Amygdala Depression, pBS LP03subtracted H6AS HI-60, untreated, subtracted Uni-ZAP XR LP03 H6ES HL-60,PMA 4 H, subtracted Uni-ZAP XR LP03 H6BS HL-60, RA 4 h, SubtractedUni-ZAP XR LP03 H6CS HL-60, PMA 1 d, subtracted Uni-ZAP XR LP03 HTXJHTXK Activated T- Uni-ZAP XR LP03 cell(12 h)/Thiouridine-re-excisionHMSA HMSB HMSC HMSD Monocyte activated Uni-ZAP XR LP03 HMSE HMSF HMSGHMSH HMSI HMSJ HMSK HAGA HAGB HAGC HAGD Human Amygdala Uni-ZAP XR LP03HAGE HAGF HSRA HSRB HSRE STROMAL - Uni-ZAP XR LP03 OSTEOCLASTOMA HSRDHSRF HSRG HSRH Human Osteoclastoma Stromal Uni-ZAP XR LP03 Cells -unamplified HSQA HSQB HSQC HSQD Stromal cell TF274 Uni-ZAP XR LP03 HSQEHSQF HSQG HSKA HSKB HSKC HSKD Smooth muscle, serum treated Uni-ZAP XRLP03 HSKE HSKF HSKZ HSLA HSLB HSLC HSLD Smooth muscle, control Uni-ZAPXR LP03 HSLE HSLF HSLG HSDA HSDD HSDE HSDF Spinal cord Uni-ZAP XR LP03HSDG HSDH HPWS Prostate-BPH subtracted II pBS LP03 HSKW HSKX HSKY SmoothMuscle - HASTE pBS LP03 normalized HFPB HFPC HFPD H. Frontal cortex,epileptic; re- Uni-ZAP XR LP03 excision HSDI HSDJ HSDK Spinal Cord,re-excision Uni-ZAP XR LP03 HSKN HSKO Smooth Muscle Serum Treated, pBSLP03 Norm HSKG HSKH HSKI Smooth muscle, serum pBS LP03 induced, re-excHFCA HFCB HFCC HFCD Human Fetal Brain Uni-ZAP XR LP04 HFCE HFCF HPTAHPTB HPTD Human Pituitary Uni-ZAP XR LP04 HTHB HTHC HTHD Human ThymusUni-ZAP XR LP04 HE6B HE6C HE6D HE6E Human Whole Six Week Old Uni-ZAP XRLP04 HE6F HE6G HE6S Embryo HSSA HSSB HSSC HSSD Human Synovial SarcomaUni-ZAP XR LP04 HSSE HSSF HSSG HSSH HSSI HSSJ HSSK HB7T 7 Week Old EarlyStage Human, Uni-ZAP XR LP04 subtracted HEPA HEPB HEPC Human EpididymusUni-ZAP XR LP04 HSNA HSNB HSNC HSNM Human Synovium Uni-ZAP XR LP04 HSNNHPFB HPFC HPFD HPFE Human Prostate Cancer, Stage C Uni-ZAP XR LP04fraction HE2A HE2D HE2E HE2H 12 Week Old Early Stage Human Uni-ZAP XRLP04 HE2I HE2M HE2N HE2O HE2B HE2C HE2F HE2G 12 Week Old Early StageHuman, Uni-ZAP XR LP04 HE2P HE2Q II HPTS HPTT HPTU Human Pituitary,subtracted Uni-ZAP XR LP04 HAUA HAUB HAUC Amniotic Cells - TNF inducedUni-ZAP XR LP04 HAQA HAQB HAQC HAQD Amniotic Cells - Primary CultureUni-ZAP XR LP04 HWTA HWTB HWTC wilm's tumor Uni-ZAP XR LP04 HBSD BoneCancer, re-excision Uni-ZAP XR LP04 HSGB Salivary gland, re-excisionUni-ZAP XR LP04 HSJA HSJB HSJC Smooth muscle-ILb induced Uni-ZAP XR LP04HSXA HSXB HSXC HSXD Human Substantia Nigra Uni-ZAP XR LP04 HSHA HSHBHSHC Smooth muscle, IL1b induced Uni-ZAP XR LP04 HOUA HOUB HOUC HOUDAdipocytes Uni-ZAP XR LP04 HOUE HPWA HPWB HPWC HPWD Prostate BPH Uni-ZAPXR LP04 HPWE HELA HELB HELC HELD Endothelial cells-control Uni-ZAP XRLP04 HELE HELF HELG HELH HEMA HEMB HEMC HEMD Endothelial-induced Uni-ZAPXR LP04 HEME HEMF HEMG HEMH HBIA HBIB HBIC Human Brain, Striatum Uni-ZAPXR LP04 HHSA HHSB HHSC HHSD Human Uni-ZAP XR LP04 HHSE Hypothalmus,Schizophrenia HNGA HNGB HNGC HNGD neutrophils control Uni-ZAP XR LP04HNGE HNGF HNGG HNGH HNGI HNGJ HNHA HNHB HNHC HNHD Neutrophils IL-1 andLPS Uni-ZAP XR LP04 HNHE HNHF HNHG HNHH induced HNHI HNHJ HSDB HSDCSTRIATUM DEPRESSION Uni-ZAP XR LP04 HHPT Hypothalamus Uni-ZAP XR LP04HSAT HSAU HSAV HSAW Anergic T-cell Uni-ZAP XR LP04 HSAX HSAY HSAZ HBMSHBMT HBMU HBMV Bone marrow Uni-ZAP XR LP04 HBMW HBMX HOEA HOEB HOEC HOEDOsteoblasts Uni-ZAP XR LP04 HOEE HOEF HOEJ HAIA HAIB HAIC HAIDEpithelial-TNFa and INF induced Uni-ZAP XR LP04 HAIE HAIF HTGA HTGB HTGCHTGD Apoptotic T-cell Uni-ZAP XR LP04 HMCA HMCB HMCC HMCDMacrophage-oxLDL Uni-ZAP XR LP04 HMCE HMAA HMAB HMAC HMAD Macrophage(GM-CSF treated) Uni-ZAP XR LP04 HMAE HMAF HMAG HPHA Normal ProstateUni-ZAP XR LP04 HPIA HPIB HPIC LNCAP prostate cell line Uni-ZAP XR LP04HPJA HPJB HPJC PC3 Prostate cell line Uni-ZAP XR LP04 HOSE HOSF HOSGHuman Osteoclastoma, re- Uni-ZAP XR LP04 excision HTGE HTGF ApoptoticT-cell, re-excision Uni-ZAP XR LP04 HMAJ HMAK H Macrophage (GM-CSFUni-ZAP XR LP04 treated), re-excision HACB HACC HACD Human AdiposeTissue, re- Uni-ZAP XR LP04 excision HFPA H. Frontal Cortex, EpilepticUni-ZAP XR LP04 HFAA HFAB HFAC HFAD Alzheimer's, spongy change Uni-ZAPXR LP04 HFAE HFAM Frontal Lobe, Dementia Uni-ZAP XR LP04 HMIA HMIB HMICHuman Manic Depression Tissue Uni-ZAP XR LP04 HTSA HTSE HTSF HTSG HumanThymus pBS LP05 HTSH HPBA HPBB HPBC HPBD Human Pineal Gland pBS LP05HPBE HSAA HSAB HSAC HSA 172 Cells pBS LP05 HSBA HSBB HSBC HSBM HSC172cells pBS LP05 HJAA HJAB HJAC HJAD Jurkat T-cell G1 phase pBS LP05 HJBAHJBB HJBC HJBD Jurkat T-Cell, S phase pBS LP05 HAFA HAFB Aortaendothelial cells + TNF-a pBS LP05 HAWA HAWB HAWC Human White AdiposepBS LP05 HTNA HTNB Human Thyroid pBS LP05 HONA Normal Ovary,Premenopausal pBS LP05 HARA HARB Human Adult Retina pBS LP05 HLJA HLJBHuman Lung pCMVSport 1 LP06 HOFM HOFN HOFO H. Ovarian Tumor, II, OV5232pCMVSport 2.0 LP07 HOGA HOGB HOGC OV 10-3-95 pCMVSport 2.0 LP07 HCGLCD34+cells, II pCMVSport 2.0 LP07 HDLA Hodgkin's Lymphoma I pCMVSport2.0 LP07 HDTA HDTB HDTC HDTD Hodgkin's Lymphoma II pCMVSport 2.0 LP07HDTE HKAA HKAB HKAC HKAD Keratinocyte pCMVSport2.0 LP07 HKAE HKAF HKAGHKAH HCIM CAPFINDER, Crohn's Disease, pCMVSport 2.0 LP07 lib 2 HKALKeratinocyte, lib 2 pCMVSport2.0 LP07 HKAT Keratinocyte, lib 3pCMVSport2.0 LP07 HNDA Nasal polyps pCMVSport2.0 LP07 HDRA H. PrimaryDendritic Cells, lib 3 pCMVSport2.0 LP07 HOHA HOHB HOHC HumanOsteoblasts II pCMVSport2.0 LP07 HLDA HLDB HLDC Liver, HepatomapCMVSport3.0 LP08 HLDN HLDO HLDP Human Liver, normal pCMVSport3.0 LP08HMTA pBMC stimulated w/ poly I/C pCMVSport3.0 LP08 HNTA NTERA2, controlpCMVSport3.0 LP08 HDPA HDPB HDPC HDPD Primary Dendritic Cells, lib 1pCMVSport3.0 LP08 HDPF HDPG HDPH HDPI HDPJ HDPK HDPM HDPN HDPO HDPPPrimary Dendritic cells, frac 2 pCMVSport3.0 LP08 HMUA HMUB HMUC MyoloidProgenitor Cell Line pCMVSport3.0 LP08 HHEA HHEB HHEC HHED T Cell helperI pCMVSport3.0 LP08 HHEM HHEN HHEO HHEP T cell helper II pCMVSport3.0LP08 HEQA HEQB HEQC Human endometrial stromal cells pCMVSport3.0 LP08HJMA HJMB Human endometrial stromal cells- pCMVSport3.0 LP08 treatedwith progesterone HSWA HSWB HSWC Human endometrial stromal cells-pCMVSport3.0 LP08 treated with estradiol HSYA HSYB HSYC Human ThymusStromal Cells pCMVSport3.0 LP08 HLWA HLWB HLWC Human PlacentapCMVSport3.0 LP08 HRAA HRAB HRAC Rejected Kidney, lib 4 pCMVSport3.0LP08 HMTM PCR, pBMC I/C treated PCRII LP09 HMJA H. Meniingima, M6 pSport1 LP10 HMKA HMKB HMKC HMKD H. Meningima, M1 pSport 1 LP10 HMKE HUSG HUSIHuman umbilical vein endothelial pSport 1 LP10 cells, IL-4 induced HUSXHUSY Human Umbilical Vein pSport 1 LP10 Endothelial Cells, uninducedHOFA Ovarian Tumor I, OV5232 pSport 1 LP10 HCFA HCFB HCFC HCFD T-CellPHA 16 hrs pSport 1 LP10 HCFL HCFM HCFN HCFO T-Cell PHA 24 hrs pSport 1LP10 HADA HADC HADD HADE Human Adipose pSport 1 LP10 HADF HADG HOVA HOVBHOVC Human Ovary pSport 1 LP10 HTWB HTWC HTWD HTWE Resting T-CellLibrary, II pSport 1 LP10 HTWF HMMA Spleen metastic melanoma pSport 1LP10 HLYA HLYB HLYC HLYD Spleen, Chronic lymphocytic pSport 1 LP10 HLYEleukemia HCGA CD34+ cell, I pSport 1 LP10 HEOM HEON Human EosinophilspSport 1 LP10 HTDA Human Tonsil, Lib 3 pSport 1 LP10 HSPA SalivaryGland, Lib 2 pSport 1 LP10 HCHA HCHB HCHC Breast Cancer cell line, MDA36 pSport 1 LP10 HCHM HCHN Breast Cancer Cell line, pSport 1 LP10angiogenic HCIA Crohn's Disease pSport 1 LP10 HDAA HDAB HDAC HEL cellline pSport 1 LP10 HABA Human Astrocyte pSport 1 LP10 HUFA HUFB HUFCUlcerative Colitis pSport 1 LP10 HNTM NTERA2 + retinoic acid, 14 dayspSport 1 LP10 HDQA Primary Dendritic pSport 1 LP10 cells, CapFinder2,frac 1 HDQM Primary Dendritic Cells, pSport 1 LP10 CapFinder, frac 2HLDX Human Liver, normal, CapFinder pSport 1 LP10 HULA HULB HULC HumanDermal Endothelial pSport1 LP10 Cells, untreated HUMA Human DermalEndothelial pSport1 LP10 cells, treated HCJA Human Stromal EndometrialpSport1 LP10 fibroblasts, untreated HCJM Human Stromal endometrialpSport1 LP10 fibroblasts, treated w/ estradiol HEDA Human Stromalendometrial pSport1 LP10 fibroblasts, treated with progesterone HFNAHuman ovary tumor cell pSport1 LP10 OV350721 HKGA HKGB HKGC HKGD MerkelCells pSport1 LP10 HISA HISB HISC Pancreas Islet Cell Tumor pSport1 LP10HLSA Skin, burned pSport1 LP10 HBZA Prostate, BPH, Lib 2 pSport 1 LP10HBZS Prostate BPH, Lib 2, subtracted pSport 1 LP10 HFIA HFIB HFICSynovial Fibroblasts (control) pSport 1 LP10 HFIH HFII HFIJ Synovialhypoxia pSport 1 LP10 HFIT HFIU HFIV Synovial IL-1/TNF stimulated pSport1 LP10 HGCA Messangial cell, frac 1 pSport1 LP10 HMVA HMVB HMVC BoneMarrow Stromal Cell, pSport1 LP10 untreated HFIX HFIY HFIZ SynovialFibroblasts (Il1/TNF), pSport1 LP10 subt HFOX HFOY HFOZ Synovialhypoxia-RSF subtracted pSport1 LP10 HMQA HMQB HMQC HMQD Human ActivatedMonocytes Uni-ZAP XR LP11 HLIA HLIB HLIC Human Liver pCMVSport 1 LP012HHBA HHBB HHBC HHBD Human Heart pCMVSport 1 LP012 HHBE HBBA HBBB HumanBrain pCMVSport 1 LP012 HLJA HLJB HLJC HLJD Human Lung pCMVSport 1 LP012HLJE HOGA HOGB HOGC Ovarian Tumor pCMVSport 2.0 LP012 HTJM HumanTonsils, Lib 2 pCMVSport 2.0 LP012 HAMF HAMG KMH2 pCMVSport 3.0 LP012HAJA HAJB HAJC L428 pCMVSport 3.0 LP012 HWBA HWBB HWBC HWBD Dendriticcells, pooled pCMVSport 3.0 LP012 HWBE HWAA HWAB HWAC Human Bone Marrow,treated pCMVSport 3.0 LP012 HWAD HWAE HYAA HYAB HYAC B Cell lymphomapCMVSport 3.0 LP012 HWHG HWHH HWHI Healing groin wound, 6.5 hourspCMVSport 3.0 LP012 post incision HWHP HWHQ HWHR Healing groin wound;7.5 hours pCMVSport 3.0 LP012 post incision HARM Healing groin wound -zero hr pCMVSport 3.0 LP012 post-incision (control) HBIM Olfactoryepithelium; nasalcavity pCMVSport 3.0 LP012 HWDA Healing Abdomen wound;70&90 min pCMVSport 3.0 LP012 post incision HWEA Healing Abdomen Wound;15 pCMVSport 3.0 LP012 days post incision HWJA Healing Abdomen Wound;21&29 pCMVSport 3.0 LP012 days HNAL Human Tongue, frac 2 pSport1 LP012HMJA H. Meniingima, M6 pSport1 LP012 HMKA HMKB HMKC HMKD H. Meningima,M1 pSport1 LP012 HMKE HOFA Ovarian Tumor I, OV5232 pSport1 LP012 HCFAHCFB HCFC HCFD T-Cell PHA 16 hrs pSport1 LP012 HCFL HCFM HCFN HCFOT-Cell PHA 24 hrs pSport1 LP012 HMMA HMMB HMMC Spleen metastic melanomapSport1 LP012 HTDA Human Tonsil, Lib 3 pSport1 LP012 HDBA Human FetalThymus pSport1 LP012 HDUA Pericardium pSport1 LP012 HBZA Prostate, BPH,Lib 2 pSport1 LP012 HWCA Larynx tumor pSport1 LP012 HWKA Normal lungpSport1 LP012 HSMB Bone marrow stroma, treated pSport1 LP012 HBHM Normaltrachea pSport1 LP012 HLFC Human Larynx pSport1 LP012 HLRB SiebbenPolyposis pSport1 LP012 HNIA Mammary Gland pSport1 LP012 HNJB Palatecarcinoma pSport1 LP012 HNKA Palate normal pSport1 LP012 HMZA Pharynxcarcinoma pSport1 LP012 HABG Cheek Carcinoma pSport1 LP012 HMZM PharynxCarcinoma pSport1 LP012 HDRM Larynx Carcinoma pSport1 LP012 HVAAPancreas normal PCA4 No pSport1 LP012 HICA Tongue carcinoma pSport1LP012 HUKA HUKB HUKC HUKD Human Uterine Cancer Lambda ZAP II LP013 HUKEHFFA Human Fetal Brain, random Lambda ZAP II LP013 primed HTUA ActivatedT-cell labeled with 4- Lambda ZAP II LP013 thioluri HBQA Early StageHuman Brain, Lambda ZAP II LP013 random primed HMEB Human microvascularEndothelial Lambda ZAP II LP013 cells, fract. B HUSH Human UmbilicalVein Lambda ZAP II LP013 Endothelial cells, fract. A, re- excision HLQCHLQD Hepatocellular tumor, re-excision Lambda ZAP II LP013 HTWJ HTWKHTWL Resting T-cell, re-excision Lambda ZAP II LP013 HF6S Human Whole 6week Old pBluescript LP013 Embryo (II), subt HHPS Human Hippocampus,subtracted pBluescript LP013 HL1S LNCAP, differential expressionpBluescript LP013 HLHS HLHT Early Stage Human Lung, pBluescript LP013Subtracted HSUS Supt cells, cyclohexamide treated, pBluescript LP013subtracted HSUT Supt cells, cyclohexamide treated, pBluescript LP013differentially expressed HSDS H. Striatum Depression, pBluescript LP013subtracted HPTZ Human Pituitary, Subtracted VII pBluescript LP013 HSDXH. Striatum Depression, subt II pBluescript LP013 HSDZ H. StriatumDepression, subt pBluescript LP013 HPBA HPBB HPBC HPBD Human PinealGland pBluescript SK− LP013 HPBE HRTA Colorectal Tumor pBluescript SK−LP013 HSBA HSBB HSBC HSBM HSC172 cells pBluescript SK− LP013 HJAA HJABHJAC HJAD Jurkat T-cell G1 phase pBluescript SK− LP013 HJBA HJBB HJBCHJBD Jurkat T-cell, S1 phase pBluescript SK− LP013 HTNA HTNB HumanThyroid pBluescript SK− LP013 HAHA HAHB Human Adult Heart Uni-ZAP XRLP013 HE6A Whole 6 week Old Embryo Uni-ZAP XR LP013 HFCA HFCB HFCC HFCDHuman Fetal Brain Uni-ZAP XR LP013 HFCE HFKC HFKD HFKE HFKF Human FetalKidney Uni-ZAP XR LP013 HFKG HGBA HGBD HGBE HGBF Human Gall BladderUni-ZAP XR LP013 HGBG HPRA HPRB HPRC HPRD Human Prostate Uni-ZAP XRLP013 HTEA HTEB HTEC HTED Human Testes Uni-ZAP XR LP013 HTEE HTTA HTTBHTTC HTTD Human Testes Tumor Uni-ZAP XR LP013 HTTE HYBA HYBB Human FetalBone Uni-ZAP XR LP013 HFLA Human Fetal Liver Uni-ZAP XR LP013 HHFB HHFCHHFD HHFE Human Fetal Heart Uni-ZAP XR LP013 HHFF HUVB HUVC HUVD HUVEHuman Umbilical Vein, End. Uni-ZAP XR LP013 remake HTHB HTHC HTHD HumanThymus Uni-ZAP XR LP013 HSTA HSTB HSTC HSTD Human Skin Tumor Uni-ZAP XRLP013 HTAA HTAB HTAC HTAD Human Activated T-cells Uni-ZAP XR LP013 HTAEHFEA HFEB HFEC Human Fetal Epithelium (skin) Uni-ZAP XR LP013 HJPA HJPBHJPC HJPD Human Jurkat Membrane Bound Uni-ZAP XR LP013 Polysomes HESAHuman Epithelioid Sarcoma Uni-ZAP XR LP013 HALS Human Adult Liver,Subtracted Uni-ZAP XR LP013 HFTA HFTB HFTC HFTD Human Fetal Dura MaterUni-ZAP XR LP013 HCAA HCAB HCAC Cem cells, cyclohexamide treated Uni-ZAPXR LP013 HRGA HRGB HRGC HRGD Raji Cells, cyclohexamide treated Uni-ZAPXR LP013 HE9A HE9B HE9C HE9D Nine Week Old Early Stage Uni-ZAP XR LP013HE9E Human HSFA Human Fibrosarcoma Uni-ZAP XR LP013 HATA HATB HATC HATDHuman Adrenal Gland Tumor Uni-ZAP XR LP013 HATE HTRA Human Trachea TumorUni-ZAP XR LP013 HE2A HE2D HE2E HE2H 12 Week Old Early Stage HumanUni-ZAP XR LP013 HE2I HE2B HE2C HE2F HE2G 12 Week Old Early Stage Human,Uni-ZAP XR LP013 HE2P II HNEA HNEB HNEC HNED Human Neutrophil Uni-ZAP XRLP013 HNEE HBGA Human Primary Breast Cancer Uni-ZAP XR LP013 HPTS HPTTHPTU Human Pituitary, subtracted Uni-ZAP XR LP013 HMQA HMQB HMQC HMQDHuman Activated Monocytes Uni-ZAP XR LP013 HOAA HOAB HOAC HumanOsteosarcoma Uni-ZAP XR LP013 HTOA HTOD HTOE HTOF human tonsils Uni-ZAPXR LP013 HTOG HMGB Human OB MG63 control Uni-ZAP XR LP013 fraction IHOPB Human OB HOS control fraction I Uni-ZAP XR LP013 HOQB Human OB HOStreated (1 nM Uni-ZAP XR LP013 E2) fraction I HAUA HAUB HAUC AmnioticCells - TNF induced Uni-ZAP XR LP013 HAQA HAQB HAQC HAQD AmnioticCells - Primary Culture Uni-ZAP XR LP013 HROA HROC HUMAN STOMACH Uni-ZAPXR LP013 HBJA HBJB HBJC HBJD HUMAN B CELL LYMPHOMA Uni-ZAP XR LP013 HBJEHODA HODB HODC HODD human ovarian cancer Uni-ZAP XR LP013 HCPA CorpusCallosum Uni-ZAP XR LP013 HSOA stomach cancer (human) Uni-ZAP XR LP013HERA SKIN Uni-ZAP XR LP013 HMDA Brain-medulloblastoma Uni-ZAP XR LP013HGLA HGLB HGLD Glioblastoma Uni-ZAP XR LP013 HWTA HWTB HWTC wilm's tumorUni-ZAP XR LP013 HEAA H. Atrophic Endometrium Uni-ZAP XR LP013 HAPN HAPOHAPP HAPQ Human Adult Pulmonary; re- Uni-ZAP XR LP013 HAPR excision HLTGHLTH Human T-cell lymphoma; re- Uni-ZAP XR LP013 excision HAHC HAHD HAHEHuman Adult Heart; re-excision Uni-ZAP XR LP013 HAGA HAGB HAGC HAGDHuman Amygdala Uni-ZAP XR LP013 HAGE HSJA HSJB HSJC Smooth muscle-ILbinduced Uni-ZAP XR LP013 HSHA HSHB HSHC Smooth muscle, IL1b inducedUni-ZAP XR LP013 HPWA HPWB HPWC HPWD Prostate BPH Uni-ZAP XR LP013 HPWEHPIA HPIB HPIC LNCAP prostate cell line Uni-ZAP XR LP013 HPJA HPJB HPJCPC3 Prostate cell line Uni-ZAP XR LP013 HBTA Bone Marrow Stroma, TNF&LPSUni-ZAP XR LP013 ind HMCF HMCG HMCH HMCI Macrophage-oxLDL; re-excisionUni-ZAP XR LP013 HMCJ HAGG HAGH HAGI Human Amygdala; re-excision Uni-ZAPXR LP013 HACA H. Adipose Tissue Uni-ZAP XR LP013 HKFB K562 + PMA (36hrs), re-excision ZAP Express LP013 HCWT HCWU HCWV CD34 positive cells(cord ZAP Express LP013 blood), re-ex HBWA Whole brain ZAP Express LP013HBXA HBXB HBXC HBXD Human Whole Brain #2 - Oligo ZAP Express LP013 dT >1.5 Kb HAVM Temporal cortex-Alzheizmer pT-Adv LP014 HAVT Hippocampus,Alzheimer pT-Adv LP014 Subtracted HHAS CHME Cell Line Uni-ZAP XR LP014HAJR Larynx normal pSport 1 LP014 HWLE HWLF HWLG HWLH Colon NormalpSport 1 LP014 HCRM HCRN HCRO Colon Carcinoma pSport 1 LP014 HWLI HWLJHWLK Colon Normal pSport 1 LP014 HWLQ HWLR HWLS HWLT Colon Tumor pSport1 LP014 HBFM Gastrocnemius Muscle pSport 1 LP014 HBOD HBOE QuadricepsMuscle pSport 1 LP014 HBKD HBKE Soleus Muscle pSport 1 LP014 HCCMPancreatic Langerhans pSport 1 LP014 HWGA Larynx carcinoma pSport 1LP014 HWGM HWGN Larynx carcinoma pSport 1 LP014 HWLA HWLB HWLC Normalcolon pSport 1 LP014 HWLM HWLN Colon Tumor pSport 1 LP014 HVAM HVAN HVAOPancreas Tumor pSport 1 LP014 HWGQ Larynx carcinoma pSport 1 LP014 HAQMHAQN Salivary Gland pSport 1 LP014 HASM Stomach; normal pSport 1 LP014HBCM Uterus; normal pSport 1 LP014 HCDM Testis; normal pSport 1 LP014HDJM Brain; normal pSport 1 LP014 HEFM Adrenal Gland, normal pSport 1LP014 HBAA Rectum normal pSport 1 LP014 HFDM Rectum tumour pSport 1LP014 HGAM Colon, normal pSport 1 LP014 HHMM Colon, tumour pSport 1LP014 HCLB HCLC Human Lung Cancer Lambda Zap II LP015 HRLA L1 Cell lineZAP Express LP015 HHAM Hypothalamus, Alzheimer's pCMVSport 3.0 LP015HKBA Ku 812F Basophils Line pSport 1 LP015 HS2S Saos2, DexamethosomeTreated pSport 1 LP016 HA5A Lung Carcinoma A549 TNFalpha pSport 1 LP016activated HTFM TF-1 Cell Line GM-CSF Treated pSport 1 LP016 HYAS ThyroidTumour pSport 1 LP016 HUTS Larynx Normal pSport 1 LP016 HXOA LarynxTumor pSport 1 LP016 HEAH Ea.hy.926 cell line pSport 1 LP016 HINAAdenocarcinoma Human pSport 1 LP016 HRMA Lung Mesothelium pSport 1 LP016HLCL Human Pre-Differentiated Uni-Zap XR LP017 Adipocytes HS2A Saos2Cells pSport 1 LP020 HS2I Saos2 Cells; Vitamin D3 Treated pSport 1 LP020HUCM CHME Cell Line, untreated pSport 1 LP020 HEPN Aryepiglottis NormalpSport 1 LP020 HPSN Sinus Piniformis Tumour pSport 1 LP020 HNSA StomachNormal pSport 1 LP020 HNSM Stomach Tumour pSport 1 LP020 HNLA LiverNormal Met5No pSport 1 LP020 HUTA Liver Tumour Met 5 Tu pSport 1 LP020HOCN Colon Normal pSport 1 LP020 HOCT Colon Tumor pSport 1 LP020 HTNTTongue Tumour pSport 1 LP020 HLXN Larynx Normal pSport 1 LP020 HLXTLarynx Tumour pSport 1 LP020 HTYN Thymus pSport 1 LP020 HPLN PlacentapSport 1 LP020 HTNG Tongue Normal pSport 1 LP020 HZAA Thyroid Normal(SDCA2 No) pSport 1 LP020 HWES Thyroid Thyroiditis pSport 1 LP020 HFHDFicolled Human Stromal Cells, pTrip1Ex2 LP021 5Fu treated HFHM, HFHNFicolled Human Stromal Cells, pTrip1Ex2 LP021 Untreated HPCI Hep G2Cells, lambda library lambda Zap- LP021 CMV XR HBCA, HBCB, HBCC H. Lymphnode breast Cancer Uni-ZAP XR LP021 HCOK Chondrocytes pSPORT1 LP022HDCA, HDCB, HDCC Dendritic Cells From CD34 Cells pSPORT1 LP022 HDMA,HDMB CD40 activated monocyte pSPORT1 LP022 dendritic cells HDDM, HDDN,HDDO LPS activated derived dendritic pSPORT1 LP022 cells HPCR Hep G2Cells, PCR library lambda Zap- LP022 CMV XR HAAA, HAAB, HAAC Lung,Cancer (4005313A3): pSPORT1 LP022 Invasive Poorly Differentiated LungAdenocarcinoma HIPA, HIPB, HIPC Lung, Cancer (4005163 B7): pSPORT1 LP022Invasive, Poorly Diff. Adenocarcinoma, Metastatic HOOH, HOOI Ovary,Cancer: (4004562 B6) pSPORT1 LP022 Papillary Serous Cystic Neoplasm, LowMalignant Pot HIDA Lung, Normal: (4005313 B1) pSPORT1 LP022 HUJA, HUJB,HUJC, HUJD, HUJE B-Cells pCMVSport 3.0 LP022 HNOA, HNOB, HNOC, HNODOvary, Normal: (9805C040R) pSPORT1 LP022 HNLM Lung, Normal: (4005313 B1)pSPORT1 LP022 HSCL Stromal Cells pSPORT1 LP022 HAAX Lung, Cancer:(4005313 A3) pSPORT1 LP022 Invasive Poorly-differentiated Metastaticlung adenocarcinoma HUUA, HUUB, HUUC, HUUD B-cells (unstimulated)pTrip1Ex2 LP022 HWWA, HWWB, HWWC, HWWD, B-cells (stimulated) pSPORT1LP022 HWWE, HWWF, HWWG HCCC Colon, Cancer: (9808C064R) pCMVSport 3.0LP023 HPDO HPDP HPDQ HPDR Ovary, Cancer (9809C332): pSport 1 LP023 HPDPoorly differentiated adenocarcinoma HPCO HPCP HPCQ HPCT Ovary, Cancer(15395A1F): pSport 1 LP023 Grade II Papillary Carcinoma HOCM HOCO HOCPHOCQ Ovary, Cancer: (15799A1F) pSport 1 LP023 Poorly differentiatedcarcinoma HCBM HCBN HCBO Breast, Cancer: (4004943 A5) pSport 1 LP023HNBT HNBU HNBV Breast, Normal: (4005522B2) pSport 1 LP023 HBCP HBCQBreast, Cancer: (4005522 A2) pSport 1 LP023 HBCJ Breast, Cancer:(9806C012R) pSport 1 LP023 HSAM HSAN Stromal cells 3.88 pSport 1 LP023HVCA HVCB HVCC HVCD Ovary, Cancer: (4004332 A2) pSport 1 LP023 HSCK HSENHSEO Stromal cells (HBM3.18) pSport 1 LP023 HSCP HSCQ stromal cell clone2.5 pSport 1 LP023 HUXA Breast Cancer: (4005385 A2) pSport 1 LP023 HCOMHCON HCOO HCOP Ovary, Cancer (4004650 A3): pSport 1 LP023 HCOQWell-Differentiated Micropapillary Serous Carcinoma HBNM Breast, Cancer:(9802C020E) pSport 1 LP023 HVVA HVVB HVVC HVVD Human Bone Marrow,treated pSport 1 LP023 HVVE

Two nonlimiting examples are provided below for isolating a particularclone from the deposited sample of plasmid cDNAs cited for that clone inTable 7. First, a plasmid is directly isolated by screening the clonesusing a polynucleotide probe corresponding to the nucleotide sequence ofSEQ ID NO:X.

Particularly, a specific polynucleotide with 3040 nucleotides issynthesized using an Applied Biosystems DNA synthesizer according to thesequence reported. The oligonucleotide is labeled, for instance, with³²P-γ-ATP using T4 polynucleotide kinase and purified according toroutine methods. (E.g., Maniatis et al., Molecular Cloning: A LaboratoryManual, Cold Spring Harbor Press, Cold Spring, N.Y. (1982)). The plasmidmixture is transformed into a suitable host, as indicated above (such asXL-1 Blue (Stratagene)) using techniques known to those of skill in theart, such as those provided by the vector supplier or in relatedpublications or patents cited above. The transformants are plated on1.5% agar plates (containing the appropriate selection agent, e.g.,ampicillin) to a density of about 150 transformants (colonies) perplate. These plates are screened using Nylon membranes according toroutine methods for bacterial colony screening (e.g., Sambrook et al.,Molecular Cloning: A Laboratory Manual, 2nd Edit., (1989), Cold SpringHarbor Laboratory Press, pages 1.93 to 1.104), or other techniques knownto those of skill in the art.

Alternatively, two primers of 17-20 nucleotides derived from both endsof the nucleotide sequence of SEQ ID NO:X are synthesized and used toamplify the desired cDNA using the deposited cDNA plasmid as a template.The polymerase chain reaction is carried out under routine conditions,for instance, in 25 μl of reaction mixture with 0.5 ug of the above cDNAtemplate. A convenient reaction mixture is 1.5-5 mM MgCl₂, 0.01% (w/v)gelatin, 20 μM each of dATP, dCTP, dGTP, dTTP, 25 pmol of each primerand 0.25 Unit of Taq polymerase. Thirty five cycles of PCR (denaturationat 94° C. for 1 min; annealing at 55° C. for 1 min; elongation at 72° C.for 1 min) are performed with a Perkin-Elmer Cetus automated thermalcycler. The amplified product is analyzed by agarose gel electrophoresisand the DNA band with expected molecular weight is excised and purified.The PCR product is verified to be the selected sequence by subcloningand sequencing the DNA product.

Several methods are available for the identification of the 5′ or 3′non-coding portions of a gene which may not be present in the depositedclone. These methods include but are not limited to, filter probing,clone enrichment using specific probes, and protocols similar oridentical to 5′ and 3′ “RACE” protocols which are well known in the art.For instance, a method similar to 5′ RACE is available for generatingthe missing 5′ end of a desired full-length transcript. (Fromont-Racineet al., Nucleic Acids Res. 21(7):1683-1684 (1993)).

Briefly, a specific RNA oligonucleotide is ligated to the 5′ ends of apopulation of RNA presumably containing full-length gene RNAtranscripts. A primer set containing a primer specific to the ligatedRNA oligonucleotide and a primer specific to a known sequence of thegene of interest is used to PCR amplify the 5′ portion of the desiredfull-length gene. This amplified product may then be sequenced and usedto generate the full length gene.

This above method starts with total RNA isolated from the desiredsource, although poly-A+ RNA can be used. The RNA preparation can thenbe treated with phosphatase if necessary to eliminate 5′ phosphategroups on degraded or damaged RNA which may interfere with the later RNAligase step. The phosphatase should then be inactivated and the RNAtreated with tobacco acid pyrophosphatase in order to remove the capstructure present at the 5′ ends of messenger RNAs. This reaction leavesa 5′ phosphate group at the 5′ end of the cap cleaved RNA which can thenbe ligated to an RNA oligonucleotide using T4 RNA ligase.

This modified RNA preparation is used as a template for first strandcDNA synthesis using a gene specific oligonucleotide. The first strandsynthesis reaction is used as a template for PCR amplification of thedesired 5′ end using a primer specific to the ligated RNAoligonucleotide and a primer specific to the known sequence of the geneof interest. The resultant product is then sequenced and analyzed toconfirm that the 5′ end sequence belongs to the desired gene.

Example 2 Isolation of Genomic Clones Corresponding to a Polynucleotide

A human genomic P1 library (Genomic Systems, Inc.) is screened by PCRusing primers selected for the sequence corresponding to SEQ ID NO:Xaccording to the method described in Example 1. (See also, Sambrook.)

Example 3 Tissue Specific Expression Analysis

The Human Genome Sciences, Inc. (HGS) database is derived fromsequencing tissue and/or disease specific cDNA libraries. Librariesgenerated from a particular tissue are selected and the specific tissueexpression pattern of EST groups or assembled contigs within theselibraries is determined by comparison of the expression patterns ofthose groups or contigs within the entire database. ESTs and assembledcontigs which show tissue specific expression are selected.

The original clone from which the specific EST sequence was generated,or in the case of an assembled contig, the clone from which the 5′ mostEST sequence was generated, is obtained from the catalogued library ofclones and the insert amplified by PCR using methods known in the art.The PCR product is denatured and then transferred in 96 or 384 wellformat to a nylon membrane (Schleicher and Scheull) generating an arrayfilter of tissue specific clones. Housekeeping genes, maize genes, andknown tissue specific genes are included on the filters. These targetscan be used in signal normalization and to validate assay sensitivity.Additional targets are included to monitor probe length and specificityof hybridization.

Radioactively labeled hybridization probes are generated by first strandcDNA synthesis per the manufacturer's instructions (Life Technologies)from mRNA/RNA samples prepared from the specific tissue being analyzed(e.g., prostate, prostate cancer, ovarian, ovarian cancer, etc.). Thehybridization probes are purified by gel exclusion chromatography,quantitated, and hybridized with the array filters in hybridizationbottles at 65° C. overnight. The filters are washed under stringentconditions and signals are captured using a Fuji phosphorimager.

Data is extracted using AIS software and following backgroundsubtraction, signal normalization is performed. This includes anormalization of filter-wide expression levels between differentexperimental runs. Genes that are differentially expressed in the tissueof interest are identified.

Example 4 Chromosomal Mapping of the Polynucleotides

An oligonucleotide primer set is designed according to the sequence atthe 5′ end of SEQ ID NO:X. This primer preferably spans about 100nucleotides. This primer set is then used in a polymerase chain reactionunder the following set of conditions: 30 seconds, 95° C.; 1 minute, 56°C.; 1 minute, 70° C. This cycle is repeated 32 times followed by one 5minute cycle at 70° C. Human, mouse, and hamster DNA is used as templatein addition to a somatic cell hybrid panel containing individualchromosomes or chromosome fragments (Bios, Inc). The reactions areanalyzed on either 8% polyacrylamide gels or 3.5% agarose gels.Chromosome mapping is determined by the presence of an approximately 100bp PCR fragment in the particular somatic cell hybrid.

Example 5 Bacterial Expression of a Polypeptide

A polynucleotide encoding a polypeptide of the present invention isamplified using PCR oligonucleotide primers corresponding to the 5′ and3′ ends of the DNA sequence, as outlined in Example 1, to synthesizeinsertion fragments. The primers used to amplify the cDNA insert shouldpreferably contain restriction sites, such as BamHI and XbaI, at the 5′end of the primers in order to clone the amplified product into theexpression vector. For example, BamHI and XbaI correspond to therestriction enzyme sites on the bacterial expression vector pQE-9.(Qiagen, Inc., Chatsworth, Calif.). This plasmid vector encodesantibiotic resistance (Amp^(r)), a bacterial origin of replication(ori), an IPTG-regulatable promoter/operator (P/O), a ribosome bindingsite (RBS), a 6-histidine tag (6-His), and restriction enzyme cloningsites.

The pQE-9 vector is digested with BamHI and XbaI and the amplifiedfragment is ligated into the pQE-9 vector maintaining the reading frameinitiated at the bacterial RBS. The ligation mixture is then used totransform the E. coli strain M15/rep4 (Qiagen, Inc.) which containsmultiple copies of the plasmid pREP4, which expresses the lacI repressorand also confers kanamycin resistance (Kan^(r)). Transformants areidentified by their ability to grow on LB plates andampicillin/kanamycin resistant colonies are selected. Plasmid DNA isisolated and confirmed by restriction analysis.

Clones containing the desired constructs are grown overnight (O/N) inliquid culture in LB media supplemented with both Amp (100 ug/ml) andKan (25 ug/ml). The O/N culture is used to inoculate a large culture ata ratio of 1:100 to 1:250. The cells are grown to an optical density 600(O.D.⁶⁰⁰) of between 0.4 and 0.6. IPTG (Isopropyl-B-D-thiogalactopyranoside) is then added to a final concentration of 1 mM. IPTG inducesby inactivating the lacI repressor, clearing the P/O leading toincreased gene expression.

Cells are grown for an extra 3 to 4 hours. Cells are then harvested bycentrifugation (20 mins at 6000×g). The cell pellet is solubilized inthe chaotropic agent 6 Molar Guanidine HCl by stirring for 3-4 hours at4° C. The cell debris is removed by centrifugation, and the supernatantcontaining the polypeptide is loaded onto a nickel-nitrilo-tri-aceticacid (“Ni-NTA”) affinity resin column (available from QIAGEN, Inc.,supra). Proteins with a 6×His tag bind to the Ni-NTA resin with highaffinity and can be purified in a simple one-step procedure (for detailssee: The QIAexpressionist (1995) QIAGEN, Inc., supra).

Briefly, the supernatant is loaded onto the column in 6 M guanidine-HCl,pH 8. The column is first washed with 10 volumes of 6 M guanidine-HCl,pH 8, then washed with 10 volumes of 6 M guanidine-HCl pH 6, and finallythe polypeptide is eluted with 6 M guanidine-HCl, pH 5.

The purified protein is then renatured by dialyzing it againstphosphate-buffered saline (PBS) or 50 mM Na-acetate, pH 6 buffer plus200 mM NaCl. Alternatively, the protein can be successfully refoldedwhile immobilized on the Ni-NTA column. The recommended conditions areas follows: renature using a linear 6M-1M urea gradient in 500 mM NaCl,20% glycerol, 20 mM Tris/HCl pH 7.4, containing protease inhibitors. Therenaturation should be performed over a period of 1.5 hours or more.After renaturation the proteins are eluted by the addition of 250 mMimmidazole. Immidazole is removed by a final dialyzing step against PBSor 50 mM sodium acetate pH 6 buffer plus 200 mM NaCl. The purifiedprotein is stored at 4° C. or frozen at −80° C.

In addition to the above expression vector, the present inventionfurther includes an expression vector, called pHE4a (ATCC AccessionNumber 209645, deposited on Feb. 25, 1998) which contains phage operatorand promoter elements operatively linked to a polynucleotide of thepresent invention, called pHE4a. (ATCC Accession Number 209645,deposited on Feb. 25, 1998.) This vector contains: 1) aneomycinphosphotransferase gene as a selection marker, 2) an E. coliorigin of replication, 3) a T5 phage promoter sequence, 4) two lacoperator sequences, 5) a Shine-Delgarno sequence, and 6) the lactoseoperon repressor gene (lacIq). The origin of replication (oriC) isderived from pUC19 (LTI, Gaithersburg, Md.). The promoter and operatorsequences are made synthetically.

DNA can be inserted into the pHE4a by restricting the vector with NdeIand XbaI, BamHI, XhoI, or Asp718, running the restricted product on agel, and isolating the larger fragment (the stuffer fragment should beabout 310 base pairs). The DNA insert is generated according to the PCRprotocol described in Example 1, using PCR primers having restrictionsites for NdeI (5′ primer) and XbaI, BamHI, XhoI, or Asp718 (3′ primer).The PCR insert is gel purified and restricted with compatible enzymes.The insert and vector are ligated according to standard protocols.

The engineered vector could easily be substituted in the above protocolto express protein in a bacterial system.

Example 6 Purification of a Polypeptide from an Inclusion Body

The following alternative method can be used to purify a polypeptideexpressed in E coli when it is present in the form of inclusion bodies.Unless otherwise specified, all of the following steps are conducted at4-10° C.

Upon completion of the production phase of the E. coli fermentation, thecell culture is cooled to 4-10° C. and the cells harvested by continuouscentrifugation at 15,000 rpm (Heraeus Sepatech). On the basis of theexpected yield of protein per unit weight of cell paste and the amountof purified protein required, an appropriate amount of cell paste, byweight, is suspended in a buffer solution containing 100 mM Tris, 50 mMEDTA, pH 7.4. The cells are dispersed to a homogeneous suspension usinga high shear mixer.

The cells are then lysed by passing the solution through amicrofluidizer (Microfuidics, Corp. or APV Gaulin, Inc.) twice at4000-6000 psi. The homogenate is then mixed with NaCl solution to afinal concentration of 0.5 M NaCl, followed by centrifugation at 7000×gfor 15 min. The resultant pellet is washed again using 0.5M NaCl, 100 mMTris, 50 mM EDTA, pH 7.4.

The resulting washed inclusion bodies are solubilized with 1.5 Mguanidine hydrochloride (GuHCl) for 24 hours. After 7000×gcentrifugation for 15 min., the pellet is discarded and the polypeptidecontaining supernatant is incubated at 4° C. overnight to allow furtherGuHCl extraction.

Following high speed centrifugation (30,000×g) to remove insolubleparticles, the GuHCl solubilized protein is refolded by quickly mixingthe GuHCl extract with 20 volumes of buffer containing 50 mM sodium, pH4.5, 150 mM NaCl, 2 mM EDTA by vigorous stirring. The refolded dilutedprotein solution is kept at 4° C. without mixing for 12 hours prior tofurther purification steps.

To clarify the refolded polypeptide solution, a previously preparedtangential filtration unit equipped with 0.16 μm membrane filter withappropriate surface area (e.g., Filtron), equilibrated with 40 mM sodiumacetate, pH 6.0 is employed. The filtered sample is loaded onto a cationexchange resin (e.g., Poros HS-50, Perseptive Biosystems). The column iswashed with 40 mM sodium acetate, pH 6.0 and eluted with 250 mM, 500 mM,1000 mM, and 1500 mM NaCl in the same buffer, in a stepwise manner. Theabsorbance at 280 nm of the effluent is continuously monitored.Fractions are collected and further analyzed by SDS-PAGE.

Fractions containing the polypeptide are then pooled and mixed with4-volumes of water. The diluted sample is then loaded onto a previouslyprepared set of tandem columns of strong anion (Poros HQ-50, PerseptiveBiosystems) and weak anion (Poros CM-20, Perseptive Biosystems) exchangeresins. The columns are equilibrated with 40 mM sodium acetate, pH 6.0.Both columns are washed with 40 mM sodium acetate, pH 6.0, 200 mM NaCl.The CM-20 column is then eluted using a 10 column volume linear gradientranging from 0.2 M NaCl, 50 mM sodium acetate, pH 6.0 to 1.0 M NaCl, 50mM sodium acetate, pH 6.5. Fractions are collected under constant A₂₈₀monitoring of the effluent. Fractions containing the polypeptide(determined, for instance, by 16% SDS-PAGE) are then pooled.

The resultant polypeptide should exhibit greater than 95% purity afterthe above refolding and purification steps. No major contaminant bandsshould be observed from Commassie blue stained 16% SDS-PAGE gel when 5μg of purified protein is loaded. The purified protein can also betested for endotoxin/LPS contamination, and typically the LPS content isless than 0.1 ng/ml according to LAL assays.

Example 7 Cloning and Expression of a Polypeptide in a BaculovirusExpression System

In this example, the plasmid shuttle vector pA2 is used to insert apolynucleotide into a baculovirus to express a polypeptide. Thisexpression vector contains the strong polyhedrin promoter of theAutographa californica nuclear polyhedrosis virus (AcMNPV) followed byconvenient restriction sites such as BamHI, Xba I and Asp718. Thepolyadenylation site of the simian virus 40 (“SV40”) is used forefficient polyadenylation. For easy selection of recombinant virus, theplasmid contains the beta-galactosidase gene from E. coli under controlof a weak Drosophila promoter in the same orientation, followed by thepolyadenylation signal of the polyhedrin gene. The inserted genes areflanked on both sides by viral sequences for cell-mediated homologousrecombination with wild-type viral DNA to generate a viable virus thatexpress the cloned polynucleotide.

Many other baculovirus vectors can be used in place of the vector above,such as pAc373, pVL941, and pAcIM1, as one skilled in the art wouldreadily appreciate, as long as the construct provides appropriatelylocated signals for transcription, translation, secretion and the like,including a signal peptide and an in-frame AUG as required. Such vectorsare described, for instance, in Luckow et al., Virology 170:31-39(1989).

Specifically, the cDNA sequence contained in the deposited clone,including the AUG initiation codon, is amplified using the PCR protocoldescribed in Example 1. If a naturally occurring signal sequence is usedto produce the polypeptide of the present invention, the pA2 vector doesnot need a second signal peptide. Alternatively, the vector can bemodified (pA2 GP) to include a baculovirus leader sequence, using thestandard methods described in Summers et al., “A Manual of Methods forBaculovirus Vectors and Insect Cell Culture Procedures,” TexasAgricultural Experimental Station Bulletin No. 1555 (1987).

The amplified fragment is isolated from a 1% agarose gel using acommercially available kit (“Geneclean,” BIO 101 Inc., La Jolla,Calif.). The fragment then is digested with appropriate restrictionenzymes and again purified on a 1% agarose gel.

The plasmid is digested with the corresponding restriction enzymes andoptionally, can be dephosphorylated using calf intestinal phosphatase,using routine procedures known in the art. The DNA is then isolated froma 1% agarose gel using a commercially available kit (“Geneclean” BIO 101Inc., La Jolla, Calif.).

The fragment and the dephosphorylated plasmid are ligated together withT4 DNA ligase. E. coli HB101 or other suitable E. coli hosts such asXL-1 Blue (Stratagene Cloning Systems, La Jolla, Calif.) cells aretransformed with the ligation mixture and spread on culture plates.Bacteria containing the plasmid are identified by digesting DNA fromindividual colonies and analyzing the digestion product by gelelectrophoresis. The sequence of the cloned fragment is confirmed by DNAsequencing.

Five μg of a plasmid containing the polynucleotide is co-transfectedwith 1.0 μg of a commercially available linearized baculovirus DNA(“BaculoGold™ baculovirus DNA, Pharmingen, San Diego, Calif.), using thelipofection method described by Felgner et al., Proc. Natl. Acad. Sci.USA 84:7413-7417 (1987). One μg of BaculoGold™ virus DNA and 5 μg of theplasmid are mixed in a sterile well of a microtiter plate containing50/1 of serum-free Grace's medium (Life Technologies Inc., Gaithersburg,Md.). Afterwards, 10 μl Lipofectin plus 90 μl Grace's medium are added,mixed and incubated for 15 minutes at room temperature. Then thetransfection mixture is added drop-wise to Sf9 insect cells (ATCC CRL1711) seeded in a 35 mm tissue culture plate with 1 ml Grace's mediumwithout serum. The plate is then incubated for 5 hours at 27° C. Thetransfection solution is then removed from the plate and 1 ml of Grace'sinsect medium supplemented with 10% fetal calf serum is added.Cultivation is then continued at 27° C. for four days.

After four days the supernatant is collected and a plaque assay isperformed, as described by Summers and Smith, supra. An agarose gel with“Blue Gal” (Life Technologies Inc., Gaithersburg) is used to allow easyidentification and isolation of gal-expressing clones, which produceblue-stained plaques. (A detailed description of a “plaque assay” ofthis type can also be found in the user's guide for insect cell cultureand baculovirology distributed by Life Technologies Inc., Gaithersburg,page 9-10.) After appropriate incubation, blue stained plaques arepicked with the tip of a micropipettor (e.g., Eppendorf). The agarcontaining the recombinant viruses is then resuspended in amicrocentrifuge tube containing 200 μl of Grace's medium and thesuspension containing the recombinant baculovirus is used to infect Sf9cells seeded in 35 mm dishes. Four days later the supernatants of theseculture dishes are harvested and then they are stored at 4° C.

To verify the expression of the polypeptide, Sf9 cells are grown inGrace's medium supplemented with 10% heat-inactivated FBS. The cells areinfected with the recombinant baculovirus containing the polynucleotideat a multiplicity of infection (“MOI”) of about 2. If radiolabeledproteins are desired, 6 hours later the medium is removed and isreplaced with SF900 II medium minus methionine and cysteine (availablefrom Life Technologies Inc., Rockville, Md.). After 42 hours, 5 μCi of³⁵S-methionine and 5 μCi ³⁵S-cysteine (available from Amersham) areadded. The cells are further incubated for 16 hours and then areharvested by centrifugation. The proteins in the supernatant as well asthe intracellular proteins are analyzed by SDS-PAGE followed byautoradiography (if radiolabeled).

Microsequencing of the amino acid sequence of the amino terminus ofpurified protein may be used to determine the amino terminal sequence ofthe produced protein.

Example 8 Expression of a Polypeptide in Mammalian Cells

The polypeptide of the present invention can be expressed in a mammaliancell. A typical mammalian expression vector contains a promoter element,which mediates the initiation of transcription of mRNA, a protein codingsequence, and signals required for the termination of transcription andpolyadenylation of the transcript Additional elements include enhancers,Kozak sequences and intervening sequences flanked by donor and acceptorsites for RNA splicing. Highly efficient transcription is achieved withthe early and late promoters from SV40, the long terminal repeats (LTRs)from Retroviruses, e.g., RSV, HILVI, HIVI and the early promoter of thecytomegalovirus (CMV). However, cellular elements can also be used(e.g., the human actin promoter).

Suitable expression vectors for use in practicing the present inventioninclude, for example, vectors such as pSVL and pMSG (Pharmacia, Uppsala,Sweden), pRSVcat (ATCC 37152), pSV2dhfr (ATCC 37146), pBC12MI (ATCC67109), pCMVSport 2.0, and pCMVSport 3.0. Mammalian host cells thatcould be used include, human Hela, 293, H9 and Jurkat cells, mouseNIH3T3 and C127 cells, Cos 1, Cos 7 and CV1, quail QC1-3 cells, mouse Lcells and Chinese hamster ovary (CHO) cells.

Alternatively, the polypeptide can be expressed in stable cell linescontaining the polynucleotide integrated into a chromosome. Theco-transfection with a selectable marker such as DHFR, gpt, neomycin, orhygromycin allows the identification and isolation of the transfectedcells.

The transfected gene can also be amplified to express large amounts ofthe encoded protein. The DHFR (dihydrofolate reductase) marker is usefulin developing cell lines that carry several hundred or even severalthousand copies of the gene of interest. (See, e.g., Alt, F. W., et al.,J. Biol. Chem. 253:1357-1370 (1978); Hamlin, J. L. and Ma, C., Biochem.et Biophys. Acta, 1097:107-143 (1990); Page, M. J. and Sydenham, M. A.,Biotechnology 9:64-68 (1991)). Another useful selection marker is theenzyme glutamine synthase (GS) (Murphy et al., Biochem J. 227:277-279(1991); Bebbington et al., Bio/Technology 10:169-175 (1992). Using thesemarkers, the mammalian cells are grown in selective medium and the cellswith the highest resistance are selected. These cell lines contain theamplified gene(s) integrated into a chromosome. Chinese hamster ovary(CHO) and NSO cells are often used for the production of proteins.

Derivatives of the plasmid pSV2-dhfr (ATCC Accession No. 37146), theexpression vectors pC4 (ATCC Accession No. 209646) and pC6 (ATCCAccession No.209647) contain the strong promoter (LTR) of the RousSarcoma Virus (Cullen et al., Molecular and Cellular Biology, 438447(March, 1985)) plus a fragment of the CMV-enhancer (Boshart et al., Cell41:521-530 (1985)). Multiple cloning sites, e.g., with the restrictionenzyme cleavage sites BamHI, XbaI and Asp718, facilitate the cloning ofthe gene of interest. The vectors also contain the 3′ intron, thepolyadenylation and termination signal of the rat preproinsulin gene,and the mouse DHFR gene under control of the SV40 early promoter.

Specifically, the plasmid pC6, for example, is digested with appropriaterestriction enzymes and then dephosphorylated using calf intestinalphosphates by procedures known in the art. The vector is then isolatedfrom a 1% agarose gel.

A polynucleotide of the present invention is amplified according to theprotocol outlined in Example 1. If a naturally occurring signal sequenceis used to produce the polypeptide of the present invention, the vectordoes not need a second signal peptide. Alternatively, if a naturallyoccurring signal sequence is not used, the vector can be modified toinclude a heterologous signal sequence. (See, e.g., InternationalPublication No. WO 96/34891.)

The amplified fragment is isolated from a 1% agarose gel using acommercially available kit (“Geneclean,” BIO 101 Inc., La Jolla,Calif.). The fragment then is digested with appropriate restrictionenzymes and again purified on a 1% agarose gel.

The amplified fragment is then digested with the same restriction enzymeand purified on a 1% agarose gel. The isolated fragment and thedephosphorylated vector are then ligated with T4 DNA ligase. E coliHB101 or XL-1 Blue cells are then transformed and bacteria areidentified that contain the fragment inserted into plasmid pC6 using,for instance, restriction enzyme analysis.

Chinese hamster ovary cells lacking an active DHFR gene is used fortransfection. Five μg of the expression plasmid pC6 or pC4 iscotransfected with 0.5 μg of the plasmid pSVneo using lipofectin(Felgner et al., supra). The plasmid pSV2-neo contains a dominantselectable marker, the neo gene from Tn5 encoding an enzyme that confersresistance to a group of antibiotics including G418. The cells areseeded in alpha minus MEM supplemented with 1 mg/ml G418. After 2 days,the cells are trypsinized and seeded in hybridoma cloning plates(Greiner, Germany) in alpha minus MEM supplemented with 10, 25, or 50ng/ml of methotrexate plus 1 mg/ml G418. After about 10-14 days singleclones are trypsinized and then seeded in 6-well petri dishes or 10 mlflasks using different concentrations of methotrexate (50 nM, 100 nM,200 nM, 400 nM, 800 nM). Clones growing at the highest concentrations ofmethotrexate are then transferred to new 6-well plates containing evenhigher concentrations of methotrexate (1 μM, 2 μM, 5 μM, 10 mM, 20 mM).The same procedure is repeated until clones are obtained which grow at aconcentration of 100-200 μM. Expression of the desired gene product isanalyzed, for instance, by SDS-PAGE and Western blot or by reversedphase HPLC analysis.

Example 9 Protein Fusions

The polypeptides of the present invention are preferably fused to otherproteins. These fusion proteins can be used for a variety ofapplications. For example, fusion of the present polypeptides toHis-tag, HA-tag, protein A, IgG domains, and maltose binding proteinfacilitates purification. (See Example 5; see also EP A 394,827;Traunecker, et al., Nature 331:84-86 (1988)). Similarly, fusion toIgG-1, IgG-3, and albumin increases the halflife time in vivo. Nuclearlocalization signals fused to the polypeptides of the present inventioncan target the protein to a specific subcellular localization, whilecovalent heterodimer or homodimers can increase or decrease the activityof a fusion protein. Fusion proteins can also create chimeric moleculeshaving more than one function. Finally, fusion proteins can increasesolubility and/or stability of the fused protein compared to thenon-fused protein. All of the types of fusion proteins described abovecan be made by modifying the following protocol, which outlines thefusion of a polypeptide to an IgG molecule, or the protocol described inExample 5.

Briefly, the human Fc portion of the IgG molecule can be PCR amplified,using primers that span the 5′ and 3′ ends of the sequence describedbelow. These primers also should have convenient restriction enzymesites that will facilitate cloning into an expression vector, preferablya mammalian expression vector.

For example, if pC4 (ATCC Accession No. 209646) is used, the human Fcportion can be ligated into the BamHI cloning site. Note that the 3′BamHI site should be destroyed. Next, the vector containing the human Fcportion is re-restricted with BamHI, linearizing the vector, and apolynucleotide of the present invention, isolated by the PCR protocoldescribed in Example 1, is ligated into this BamHI site. Note that thepolynucleotide is cloned without a stop codon, otherwise a fusionprotein will not be produced.

If the naturally occurring signal sequence is used to produce thepolypeptide of the present invention, pC4 does not need a second signalpeptide. Alternatively, if the naturally occurring signal sequence isnot used, the vector can be modified to include a heterologous signalsequence. (See, e.g., International Publication No. WO 96/34891.)

Human IgG Fc region:GGGATCCGGAGCCCAAATCTTCTGACAAAACTCACACATGCCCACCGTGCCCAGCAC (SEQ ID NO: 1)CTGAATTCGAGGGTGCACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACTCCTGAGGTCACATGCGTGGTGGTGGACGTAAGCCACGAAGACCCTGAGGTCAAGTTCAAGTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAACCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCAAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAATGAGTGCGACGGCCGCGACTCTAGAGGAT

Example 10 Production of an Antibody from a Polypeptide

a) Hybridoma Technology

The antibodies of the present invention can be prepared by a variety ofmethods. (See, Current Protocols, Chapter 2.) As one example of suchmethods, cells expressing a polypeptide of the present invention areadministered to an animal to induce the production of sera containingpolyclonal antibodies. In a preferred method, a preparation of apolypeptide of the present invention is prepared and purified to renderit substantially free of natural contaminants. Such a preparation isthen introduced into an animal in order to produce polyclonal antiseraof greater specific activity.

Monoclonal antibodies specific for a polypeptide of the presentinvention are prepared using hybridoma technology (Kohler et al., Nature256:495 (1975); Kohler et al., Eur. J. Immunol. 6:511 (1976); Kohler etal., Eur. J. Immunol. 6:292 (1976); Hammerling et al., in: MonoclonalAntibodies and T-Cell Hybridomas, Elsevier, N.Y., pp. 563-681 (1981)).In general, an animal (preferably a mouse) is immunized with apolypeptide of the present invention or, more preferably, with asecreted polypeptide-expressing cell. Such polypeptide-expressing cellsare cultured in any suitable tissue culture medium, preferably inEarle's modified Eagle's medium supplemented with 10% fetal bovine serum(inactivated at about 56° C.), and supplemented with about 10 g/l ofnonessential amino acids, about 1,000 U/ml of penicillin, and about 100μg/ml of streptomycin.

The splenocytes of such mice are extracted and fused with a suitablemyeloma cell line. Any suitable myeloma cell line may be employed inaccordance with the present invention; however, it is preferable toemploy the parent myeloma cell line (SP20), available from the ATCC.After fusion, the resulting hybridoma cells are selectively maintainedin HAT medium, and then cloned by limiting dilution as described byWands et al. (Gastroenterology 80:225-232 (1981)). The hybridoma cellsobtained through such a selection are then assayed to identify cloneswhich secrete antibodies capable of binding the polypeptide of thepresent invention.

Alternatively, additional antibodies capable of binding to a polypeptideof the present invention can be produced in a two-step procedure usinganti-idiotypic antibodies. Such a method makes use of the fact thatantibodies are themselves antigens, and therefore, it is possible toobtain an antibody which binds to a second antibody. In accordance withthis method, protein specific antibodies are used to immunize an animal,preferably a mouse. The splenocytes of such an animal are then used toproduce hybridoma cells, and the hybridoma cells are screened toidentify clones which produce an antibody whose ability to bind to thepolypeptide-specific antibody can be blocked by said polypeptide. Suchantibodies comprise anti-idiotypic antibodies to thepolypeptide-specific antibody and are used to immunize an animal toinduce formation of further polypeptide-specific antibodies.

For in vivo use of antibodies in humans, an antibody is “humanized”.Such antibodies can be produced using genetic constructs derived fromhybridoma cells producing the monoclonal antibodies described above.Methods for producing chimeric and humanized antibodies are known in theart and are discussed herein. (See, for review, Morrison, Science229:1202 (1985); Oi et al., BioTecbniques 4:214 (1986); Cabilly et al.,U.S. Pat. No. 4,816,567; Taniguchi et al., EP 171496; Morrison et al.,EP 173494; Neuberger et al., WO 8601533; Robinson et al., InternationalPublication No. WO 8702671; Boulianne et al., Nature 312:643 (1984);Neuberger et al., Nature 314:268 (1985)).

b) Isolation Of Antibody Fragments Directed Against a Polypeptide of thePresent Invention From A Library Of scFvs

Naturally occurring V-genes isolated from human PBLs are constructedinto a library of antibody fragments which contain reactivities againsta polypeptide of the present invention to which the donor may or may nothave been exposed (see e.g., U.S. Pat. No. 5,885,793 incorporated hereinby reference in its entirety).

Rescue of the Library. A library of scFvs is constructed from the RNA ofhuman PBLs as described in International Publication No. WO 92/01047. Torescue phage displaying antibody fragments, approximately 10⁹ E. coliharboring the phagemid are used to inoculate 50 ml of 2×TY containing 1%glucose and 100 μg/ml of ampicillin (2xTY-AMP-GLU) and grown to an O.D.of 0.8 with shaking. Five ml of this culture is used to inoculate 50 mlof 2×TY-AMP-GLU, 2×108 TU of delta gene 3 helper (M13 delta gene III,see International Publication No. WO 92/01047) are added and the cultureincubated at 37° C. for 45 minutes without shaking and then at 37° C.for 45 minutes with shaking. The culture is centrifuged at 4000 r.p.m.for 10 min. and the pellet resuspended in 2 liters of 2×TY containing100 μg/ml ampicillin and 50 ug/ml kanamycin and grown overnight. Phageare prepared as described in International Publication No. WO 92/01047.

M13 delta gene III is prepared as follows: M13 delta gene III helperphage does not encode gene III protein, hence the phage(mid) displayingantibody fragments have a greater avidity of binding to antigen.Infectious M13 delta gene III particles are made by growing the helperphage in cells harboring a pUC19 derivative supplying the wild type geneIII protein during phage morphogenesis. The culture is incubated for 1hour at 37° C. without shaking and then for a further hour at 37° C.with shaking. Cells are spun down (IEC-Centra 8,400 r.p.m for 10 min),resuspended in 300 ml 2×TY broth containing 100 μg ampicillin/ml and 25μg kanamycin/ml (2×TY-AMP-KAN) and grown overnight, shaking at 37° C.Phage particles are purified and concentrated from the culture medium bytwo PEG-precipitations (Sambrook et al., 1990), resuspended in 2 ml PBSand passed through a 0.45 ium filter (Mnisart NML; Sartorius) to give afinal concentration of approximately 10¹³ transducing units/ml(ampicillin-resistant clones).

Panning of the Library. Immunotubes (Nunc) are coated overnight in PBSwith 4 ml of either 100 μg/ml or 10 μg/ml of a polypeptide of thepresent invention. Tubes are blocked with 2% Marvel-PBS for 2 hours at37° C. and then washed 3 times in PBS. Approximately 10¹³ TU of phage isapplied to the tube and incubated for 30 minutes at room temperaturetumbling on an over and under turntable and then left to stand foranother 1.5 hours. Tubes are washed 10 times with PBS 0.1% Tween-20 and10 times with PBS. Phage are eluted by adding 1 ml of 100 mMtriethylamine and rotating 15 minutes on an under and over turntableafter which the solution is immediately neutralized with 0.5 ml of 1.0MTris-HCl, pH 7.4. Phage are then used to infect 10 ml of mid-log E. coliTG1 by incubating eluted phage with bacteria for 30 minutes at 37° C.The E. coli are then plated on TYE plates containing 1% glucose and 100μg/ml ampicillin. The resulting bacterial library is then rescued withdelta gene 3 helper phage as described above to prepare phage for asubsequent round of selection. This process is then repeated for a totalof 4 rounds of affinity purification with tube-washing increased to 20times with PBS, 0.1% Tween-20 and 20 times with PBS for rounds 3 and 4.

Characterization of Binders. Eluted phage from the 3rd and 4th rounds ofselection are used to infect E. coli BB 2151 and soluble scFv isproduced (Marks, et al., 1991) from single colonies for assay. ELISAsare performed with microtitre plates coated with either 10 pg/ml of thepolypeptide of the present invention in 50 mM bicarbonate pH 9.6. Clonespositive in ELISA are further characterized by PCR fingerprinting (see,e.g., International Publication No. WO 92/01047) and then by sequencing.These ELISA positive clones may also be further characterized bytechniques known in the art, such as, for example, epitope mapping,binding affinity, receptor signal transduction, ability to block orcompetitively inhibit antibody/antigen binding, and competitiveagonistic or antagonistic activity.

Example 11 Method of Determining Alterations in a Gene Corresponding toa Polynucleotide

RNA isolated from entire families or individual patients presenting witha cardiovascular disease or disorder is isolated. cDNA is then generatedfrom these RNA samples using protocols known in the art. (See,Sambrook.) The cDNA is then used as a template for PCR, employingprimers surrounding regions of interest in SEQ ID NO:X; and/or thenucleotide sequence of the cDNA contained in ATCC Deposit No:Z.Suggested PCR conditions consist of 35 cycles at 95 degrees C. for 30seconds; 60-120 seconds at 52-58 degrees C.; and 60-120 seconds at 70degrees C., using buffer solutions described in Sidransky et al.,Science 252:706 (1991).

PCR products are then sequenced using primers labeled at their 5′ endwith T4 polynucleotide kinase, employing SequiTherm Polymerase(Epicentre Technologies). The intron-exon boundaries of selected exonsis also determined and genomic PCR products analyzed to confirm theresults. PCR products harboring suspected mutations are then cloned andsequenced to validate the results of the direct sequencing.

PCR products are cloned into T-tailed vectors as described in Holton etal., Nucleic Acids Research, 19:1156 (1991) and sequenced with T7polymerase (United States Biochemical). Affected individuals areidentified by mutations not present in unaffected individuals.

Genomic rearrangements are also observed as a method of determiningalterations in a gene corresponding to a polynucleotide. Genomic clonesisolated according to Example 2 are nick-translated withdigoxigenindeoxy-uridine 5′-triphosphate (Boehringer Manheim), and FISHperformed as described in Johnson et al., Methods Cell Biol. 35:73-99(1991). Hybridization with the labeled probe is carried out using a vastexcess of human cot-I DNA for specific hybridization to thecorresponding genomic locus.

Chromosomes are counterstained with 4,6-diamino-2-phenylidole andpropidium iodide, producing a combination of C- and R-bands. Alignedimages for precise mapping are obtained using a triple-band filter set(Chroma Technology, Brattleboro, Vt.) in combination with a cooledcharge-coupled device camera (Photometrics, Tucson, Ariz.) and variableexcitation wavelength filters. (Johnson et al., Genet. Anal. Tech.Appl., 8:75 (1991)). Inage collection, analysis and chromosomalfractional length measurements are performed using the ISee GraphicalProgram System. (Inovision Corporation, Durham, N.C.) Chromosomealterations of the genomic region hybridized by the probe are identifiedas insertions, deletions, and translocations. These alterations are usedas a diagnostic marker for an associated disease.

Example 12 Method of Detecting Abnormal Levels of a Polypeptide in aBiological Sample

A polypeptide of the present invention can be detected in a biologicalsample, and if an increased or decreased level of the polypeptide isdetected, this polypeptide is a marker for a particular phenotype.Methods of detection are numerous, and thus, it is understood that oneskilled in the art can modify the following assay to fit theirparticular needs.

For example, antibody-sandwich ELISAs are used to detect polypeptides ina sample, preferably a biological sample. Wells of a microtiter plateare coated with specific antibodies, at a final concentration of 0.2 to10 ug/ml. The antibodies are either monoclonal or polyclonal and areproduced by the method described in Example 10. The wells are blocked sothat non-specific binding of the polypeptide to the well is reduced.

The coated wells are then incubated for >2 hours at RT with a samplecontaining the polypeptide. Preferably, serial dilutions of the sampleshould be used to validate results. The plates are then washed threetimes with deionized or distilled water to remove unbound polypeptide.

Next, 50 ul of specific antibody-alkaline phosphatase conjugate, at aconcentration of 25400 ng, is added and incubated for 2 hours at roomtemperature. The plates are again washed three times with deionized ordistilled water to remove unbound conjugate.

Add 75 ul of 4-methylumbelliferyl phosphate (MUP) or p-nitrophenylphosphate (NPP) substrate solution to each well and incubate 1 hour atroom temperature. Measure the reaction by a microtiter plate reader.Prepare a standard curve, using serial dilutions of a control sample,and plot polypeptide concentration on the X-axis (log scale) andfluorescence or absorbance of the Y-axis (linear scale). Interpolate theconcentration of the polypeptide in the sample using the standard curve.

Example 13 Formulation

The invention also provides methods of preventing, treating and/orameliorating a cardiovascular disease or disorder by administration to asubject of an effective amount of a Therapeutic. By therapeutic is meantpolynucleotides or polypeptides of the invention (including fragmentsand variants), agonists or antagonists thereof, and/or antibodiesthereto, in combination with a pharmaceutically acceptable carrier type(e.g., a sterile carrier).

The Therapeutic will be formulated and dosed in a fashion consistentwith good medical practice, taking into account the clinical conditionof the individual patient (especially the side effects of treatment withthe Therapeutic alone), the site of delivery, the method ofadministration, the scheduling of administration, and other factorsknown to practitioners. The “effective amount” for purposes herein isthus determined by such considerations.

As a general proposition, the total pharmaceutically effective amount ofthe Therapeutic administered parenterally per dose will be in the rangeof about lug/kg/day to 10 mg/kg/day of patient body weight, although, asnoted above, this will be subject to therapeutic discretion. Morepreferably, this dose is at least 0.01 mg/kg/day, and most preferablyfor humans between about 0.01 and 1 mg/kg/day for the hormone. If givencontinuously, the Therapeutic is typically administered at a dose rateof about 1 ug/kg/hour to about 50 ug/kg/hour, either by 14 injectionsper day or by continuous subcutaneous infusions, for example, using amini-pump. An intravenous bag solution may also be employed. The lengthof treatment needed to observe changes and the interval followingtreatment for responses to occur appears to vary depending on thedesired effect.

Therapeutics can be are administered orally, rectally, parenterally,intracistemally, intravaginally, intraperitoneally, topically (as bypowders, ointments, gels, drops or transdermal patch), bucally, or as anoral or nasal spray. “Pharmaceutically acceptable carrier” refers to anon-toxic solid, semisolid or liquid filler, diluent, encapsulatingmaterial or formulation auxiliary of any. The term “parenteral” as usedherein refers to modes of administration which include intravenous,intramuscular, intraperitoneal, intrasternal, subcutaneous andintraarticular injection and infusion.

Therapeutics of the invention are also suitably administered bysustained-release systems. Suitable examples of sustained-releaseTherapeutics are administered orally, rectally, parenterally,intracistemally, intravaginally, intraperitoneally, topically (as bypowders, ointments, gels, drops or transdermal patch), bucally, or as anoral or nasal spray. “Pharmaceutically acceptable carrier” refers to anon-toxic solid, semisolid or liquid filler, diluent, encapsulatingmaterial or formulation auxiliary of any type. The term “parenteral” asused herein refers to modes of administration which include intravenous,intramuscular, intraperitoneal, intrasternal, subcutaneous andintraarticular injection and infusion.

Therapeutics of the invention are also suitably administered bysustained-release systems. Suitable examples of sustained-releaseTherapeutics include suitable polymeric materials (such as, for example,semi-permeable polymer matrices in the form of shaped articles, e.g.,films, or microcapsules), suitable hydrophobic materials (for example asan emulsion in an acceptable oil) or ion exchange resins, and sparinglysoluble derivatives (such as, for example, a sparingly soluble salt).

Sustained-release matrices include polylactides (U.S. Pat. No.3,773,919, EP 58,481), copolymers of L-glutamic acid andgamma-ethyl-L-glutamate (Sidman et al., Biopolymers 22:547-556 (1983)),poly (2-hydroxyethyl methacrylate) (Langer et al., J. Biomed. Mater.Res. 15:167-277 (1981), and Langer, Chem. Tech. 12:98-105 (1982)),ethylene vinyl acetate (Langer et al., Id.) orpoly-D-(−)-3-hydroxybutyric acid (EP 133,988).

In a preferred embodiment, polypeptide, polynucleotide, and antibodycompositions of the invention are formulated in a biodegradable,polymeric drug delivery system, for example as described in U.S. Pat.Nos. 4,938,763, 5,278,201; 5,278,202; 5,324,519; 5,340,849; and5,487,897 and in International Publication Numbers WO01/35929,WO00/24374, and WO00/06117 which are hereby incorporated by reference intheir entirety. In specific preferred embodiments the polypeptide,polynucleotide, and antibody compositions of the invention areformulated using the ATRIGEL® Biodegradable System of AtrixLaboratories, Inc. (Fort Collins, Colo.).

Examples of biodegradable polymers which can be used in the formulationof polypeptide, polynucleotide, and antibody compositions, include butare not limited to, polylactides, polyglycolides, polycaprolactones,polyanhydrides, polyamides, polyurethanes, polyesteramides,polyorthoesters, polydioxanones, polyacetals, polyketals,polycarbonates, polyorthocarbonates, polyphosphazenes,polyhydroxybutyrates, polyhydroxyvalerates, polyallylene oxalates,polyalkylene succinates, poly(malic acid), poly(amino acids),poly(methyl vinyl ether), poly(maleic anhydride), polyvinylpyrrolidone,polyethylene glycol, polyhydroxycellulose, chitin, chitosan, andcopolymers, terpolymers, or combinations or mixtures of the abovematerials. The preferred polymers are those that have a lower degree ofcrystallization and are more hydrophobic. These polymers and copolymersare more soluble in the biocompatible solvents than the highlycrystalline polymers such as polyglycolide and chitin which also have ahigh degree of hydrogen-bonding. Preferred materials with the desiredsolubility parameters are the polylactides, polycaprolactones, andcopolymers of these with glycolide in which there are more amorphousregions to enhance solubility. In specific preferred embodiments, thebiodegradable polymers which can be used in the formulation ofpolypeptide, polynucleotide, and antibody compositions arepoly(lactide-co-glycolides). Polymer properties such as molecularweight, hydrophobicity, and lactide/glycolide ratio may be modified toobtain the desired polypeptide, polynucleotide, or antibody releaseprofile (See, e.g., Ravivarapu et al., Journal of PharmaceuticalSciences 89:732-741 (2000), which is hereby incorporated by reference inits entirety).

It is also preferred that the solvent for the biodegradable polymer benon-toxic, water miscible, and otherwise biocompatible. Examples of suchsolvents include, but are not limited to, N-methyl-2-pyrrolidone,2-pyrrolidone, C2 to C6 alkanols, C1 to C15 alchohols, dils, triols, andtetraols such as ethanol, glycerine propylene glycol, butanol; C3 to C15alkyl ketones such as acetone, diethyl ketone and methyl ethyl ketone;C3 to C15 esters such as methyl acetate, ethyl acetate, ethyl lactate;alkyl ketones such as methyl ethyl ketone, C1 to C15 amides such asdimethylformamide, dimethylacetamide and caprolactam; C3 to C20 etherssuch as tetrahydrofuran, or solketal; tweens, triacetin, propylenecarbonate, decylmethylsulfoxide, dimethyl sulfoxide, oleic acid,1-dodecylazacycloheptan-2-one, Other preferred solvents are benzylalchohol, benzyl benzoate, dipropylene glycol, tributyrin, ethyl oleate,glycerin, glycofural, isopropyl myristate, isopropyl palmitate, oleicacid, polyethylene glycol, propylene carbonate, and triethyl citrate.The most preferred solvents are N-methyl-2-pyrrolidone, 2-pyrrolidone,dimethyl sulfoxide, triacetin, and propylene carbonate because of thesolvating ability and their compatibility.

Additionally, formulations comprising polypeptide, polynucleotide, andantibody compositions and a biodegradable polymer may also includerelease-rate modification agents and/or pore-forming agents. Examples ofrelease-rate modification agents include, but are not limited to, fattyacids, triglycerides, other like hydrophobic compounds, organicsolvents, plasticizing compounds and hydrophilic compounds. Suitablerelease rate modification agents include, for example, esters of mono-,di-, and tricarboxylic acids, such as 2-ethoxyethyl acetate, methylacetate, ethyl acetate, diethyl phthalate, dimethyl phthalate, dibutylphthalate, dimethyl adipate, dimethyl succinate, dimethyl oxalate,dimethyl citrate, triethyl citrate, acetyl tributyl citrate, acetyltriethyl citrate, glycerol triacetate, di(n-butyl) sebecate, and thelike; polyhydroxy alcohols, such as propylene glycol, polyethyleneglycol, glycerin, sorbitol, and the like; fatty acids; triesters ofglycerol, such as triglycerides, epoxidized soybean oil, and otherepoxidized vegetable oils; sterols, such as cholesterol; alcohols, suchas C.sub.6-C.sub.12 alkanols, 2-ethoxyethanol. The release ratemodification agent may be used singly or in combination with other suchagents. Suitable combinations of release rate modification agentsinclude, but are not limited to, glycerin/propylene glycol,sorbitol/glycerine, ethylene oxide/propylene oxide, butyleneglycol/adipic acid, and the like. Preferred release rate modificationagents include, but are not limited to, dimethyl citrate, triethylcitrate, ethyl heptanoate, glycerin, and hexanediol. Suitablepore-forming agents that may be used in the polymer composition include,but are not limited to, sugars such as sucrose and dextrose, salts suchas sodium chloride and sodium carbonate, polymers such ashydroxylpropylcellulose, carboxymethylcellulose, polyethylene glycol,and polyvinylpyrrolidone. Solid crystals that will provide a definedpore size, such as salt or sugar, are preferred.

In specific preferred embodiments the polypeptide, polynucleotide, andantibody compositions of the invention are formulated using the BEMA™BioErodible Mucoadhesive System, MCA™ MucoCutaneous Absorption System,SMP™ Solvent MicroParticle System, or BCP™ BioCompatible Polymer Systemof Atrix Laboratories, Inc. (Fort Collins, Colo.).

Sustained-release Therapeutics also include liposomally entrappedTherapeutics of the invention (see generally, Langer, Science249:1527-1533 (1990); Treat et al., in Liposomes in the Therapy ofInfectious Disease and Cancer, Lopez-Berestein and Fidler (eds.), Liss,New York, pp. 317-327 and 353-365 (1989)). Liposomes containing theTherapeutic are prepared by methods known per se: DE 3,218,121; Epsteinet al., Proc. Natl. Acad. Sci. (USA) 82:3688-3692 (1985); Hwang et al.,Proc. Natl. Acad. Sci.(USA) 77:4030-4034 (1980); EP 52,322; EP 36,676;EP 88,046; EP 143,949; EP 142,641; Japanese Pat. Appl. 83-118008; U.S.Pat. Nos. 4,485,045 and 4,544,545; and EP 102,324. Ordinarily, theliposomes are of the small (about 200-800 Angstroms) unilamellar type inwhich the lipid content is greater than about 30 mol. percentcholesterol, the selected proportion being adjusted for the optimalTherapeutic.

In yet an additional embodiment, the Therapeutics of the invention aredelivered by way of a pump (see Langer, supra; Sefton, CRC Crit. Ref.Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980);Saudek et al., N. Engl. J. Med. 321:574 (1989)).

Other controlled release systems are discussed in the review by Langer(Science 249:1527-1533 (1990)).

For parenteral administration, in one embodiment, the Therapeutic isformulated generally by mixing it at the desired degree of purity, in aunit dosage injectable form (solution, suspension, or emulsion), with apharmaceutically acceptable carrier, i.e., one that is non-toxic torecipients at the dosages and concentrations employed and is compatiblewith other ingredients of the formulation. For example, the formulationpreferably does not include oxidizing agents and other compounds thatare known to be deleterious to the Therapeutic.

Generally, the formulations are prepared by contacting the Therapeuticuniformly and intimately with liquid carriers or finely divided solidcarriers or both. Then, if necessary, the product is shaped into thedesired formulation. Preferably the carrier is a parenteral carrier,more preferably a solution that is isotonic with the blood of therecipient Examples of such carrier vehicles include water, saline,Ringer's solution, and dextrose solution. Non-aqueous vehicles such asfixed oils and ethyl oleate are also useful herein, as well asliposomes.

The carrier suitably contains minor amounts of additives such assubstances that enhance isotonicity and chemical stability. Suchmaterials are non-toxic to recipients at the dosages and concentrationsemployed, and include buffers such as phosphate, citrate, succinate,acetic acid, and other organic acids or their salts; antioxidants suchas ascorbic acid; low molecular weight (less than about ten residues)polypeptides, e.g., polyarginine or tripeptides; proteins, such as serumalbumin, gelatin, or immunoglobulins; hydrophilic polymers such aspolyvinylpyrrolidone; amino acids, such as glycine, glutamic acid,aspartic acid, or arginine; monosaccharides, disaccharides, and othercarbohydrates including cellulose or its derivatives, glucose, manose,or dextrins; chelating agents such as EDTA; sugar alcohols such asmannitol or sorbitol; counterions such as sodium; and/or nonionicsurfactants such as polysorbates, poloxamers, or PEG.

The Therapeutic is typically formulated in such vehicles at aconcentration of about 0.1 mg/ml to 100 mg/ml, preferably 1-10 mg/ml, ata pH of about 3 to 8. It will be understood that the use of certain ofthe foregoing excipients, carriers, or stabilizers will result in theformation of polypeptide salts.

Any pharmaceutical used for therapeutic administration can be sterile.Sterility is readily accomplished by filtration through sterilefiltration membranes (e.g., 0.2 micron membranes). Therapeuticsgenerally are placed into a container having a sterile access port, forexample, an intravenous solution bag or vial having a stopper pierceableby a hypodermic injection needle.

Therapeutics ordinarily will be stored in unit or multi-dose containers,for example, sealed ampoules or vials, as an aqueous solution or as alyophilized formulation for reconstitution. As an example of alyophilized formulation, 10-ml vials are filled with 5 ml ofsterile-filtered 1% (w/v) aqueous Therapeutic solution, and theresulting mixture is lyophilized. The infusion solution is prepared byreconstituting the lyophilized Therapeutic using bacteriostaticWater-for-Injection.

The invention also provides a pharmaceutical pack or kit comprising oneor more containers filled with one or more of the ingredients of theTherapeutics of the invention. Associated with such container(s) can bea notice in the form prescribed by a governmental agency regulating themanufacture, use or sale of pharmaceuticals or biological products,which notice reflects approval by the agency of manufacture, use or salefor human administration. In addition, the Therapeutics may be employedin conjunction with other therapeutic compounds.

The Therapeutics of the invention may be administered alone or incombination with adjuvants. Adjuvants that may be administered with theTherapeutics of the invention include, but are not limited to, alum,alum plus deoxycholate (ImmunoAg), MTP-PE (Biocine Corp.), QS21(Genentech, Inc.), BCG (e.g., THERACYS®), MPL and nonviable preparationsof Corynebacterium parvum. In a specific embodiment, Therapeutics of theinvention are administered in combination with alum. In another specificembodiment, Therapeutics of the invention are administered incombination with QS-21. Further adjuvants that may be administered withthe Therapeutics of the invention include, but are not limited to,Monophosphoryl lipid immunomodulator, AdjuVax 100a, QS-21, QS-18,CRL1005, Aluminum salts, MF-59, and Virosomal adjuvant technology.Vaccines that may be administered with the Therapeutics of the inventioninclude, but are not limited to, vaccines directed toward protectionagainst MMR (measles, mumps, rubella), polio, varicella,tetanus/diptheria, hepatitis A, hepatitis B, haemophilus influenzae B,whooping cough, pneumonia, influenza, Lyme's Disease, rotavirus,cholera, yellow fever, Japanese encephalitis, poliomyelitis, rabies,typhoid fever, and pertussis. Combinations may be administered eitherconcomitantly, e.g., as an admixture, separately but simultaneously orconcurrently; or sequentially. This includes presentations in which thecombined agents are administered together as a therapeutic mixture, andalso procedures in which the combined agents are administered separatelybut simultaneously, e.g., as through separate intravenous lines into thesame individual. Administration “in combination” further includes theseparate administration of one of the compounds or agents given first,followed by the second.

The Therapeutics of the invention may be administered alone or incombination with other therapeutic agents. Therapeutic agents that maybe administered in combination with the Therapeutics of the invention,include but not limited to, chemotherapeutic agents, antibiotics,steroidal and non-steroidal anti-inflammatories, conventionalimmunotherapeutic agents, and/or therapeutic treatments described below.Combinations may be administered either concomitantly, e.g., as anadmixture, separately but simultaneously or concurrently; orsequentially. This includes presentations in which the combined agentsare administered together as a therapeutic mixture, and also proceduresin which the combined agents are administered separately butsimultaneously, e.g., as through separate intravenous lines into thesame individual. Administration “in combination” further includes theseparate administration of one of the compounds or agents given first,followed by the second.

In one embodiment, the Therapeutics of the invention are administered incombination with an anticoagulant. Anticoagulants that may beadministered with the compositions of the invention include, but are notlimited to, heparin, low molecular weight heparin, warfarin sodium(e.g., COUMADIN®), dicumarol, 4-hydroxycoumarin, anisindione (e.g.,MIRADON™), acenocoumarol (e.g., nicoumalone, SINTHROME™),indan-1,3-dione, phenprocoumon (e.g., MARCUMAR™), ethyl biscoumacetate(e.g., TROMEXAN™), and aspirin. In a specific embodiment, compositionsof the invention are administered in combination with heparin and/orwarfarin. In another specific embodiment, compositions of the inventionare administered in combination with warfarin. In another specificembodiment, compositions of the invention are administered incombination with warfarin and aspirin. In another specific embodiment,compositions of the invention are administered in combination withheparin. In another specific embodiment, compositions of the inventionare administered in combination with heparin and aspirin.

In another embodiment, the Therapeutics of the invention areadministered in combination with thrombolytic drugs. Thrombolytic drugsthat may be administered with the compositions of the invention include,but are not limited to, plasminogen, lys-plasmninogen,alpha2-antiplasmin, streptokinae (e.g., KABIKINASE™), antiresplace(e.g., EMINASE™), tissue plasminogen activator (t-PA, altevase,ACTIVASE™), urokinase (e.g., ABBOKINASE™), sauruplase, (Prourokinase,single chain urolinase), and aminocaproic acid (e.g., AMICAR™). In aspecific embodiment, compositions of the invention are administered incombination with tissue plasminogen activator and aspirin.

In another embodiment, the Therapeutics of the invention areadministered in combination with antiplatelet drugs. Antiplatelet drugsthat may be administered with the compositions of the invention include,but are not limited to, aspirin, dipyridamole (e.g., PERSANTINE™), andticlopidine (e.g., TICLID™).

In specific embodiments, the use of anticoagulants, thrombolytic and/orantiplatelet drugs in combination with Therapeutics of the invention iscontemplated for the detection, prevention, diagnosis, prognostication,treatment, and/or amelioration of thrombosis, arterial thrombosis,venous thrombosis, thromboembolism, pulmonary embolism, atherosclerosis,myocardial infarction, transient ischemic attack, unstable angina. Inspecific embodiments, the use of anticoagulants, thrombolytic drugsand/or antiplatelet drugs in combination with Therapeutics of theinvention is contemplated for the prevention of occulsion of saphenousgrafts, for reducing the risk of periprocedural thrombosis as mightaccompany angioplasty procedures, for reducing the risk of stroke inpatients with atrial fibrillation including nonrheumatic atrialfibrillation, for reducing the risk of embolism associated withmechanical heart valves and or mitral valves disease. Other uses for thetherapeutics of the invention, alone or in combination withantiplatelet, anticoagulant, and/or thrombolytic drugs, include, but arenot limited to, the prevention of occlusions in extracorporeal devices(e.g., intravascular canulas, vascular access shunts in hemodialysispatients, hemodialysis machines, and cardiopulmonary bypass machines).

Therapeutics of the invention may also be administered in combinationwith additional cardiovascular agents, such as, for example,beta-adrenergic blockers, calcium channel blockers, ACE inhibitors,angiotensin II blockers, alpha adrenergic blockers, hypotensive agents,antilipemic agents, and vasodilating agents.

Non-limiting examples of beta-adrenergic blockers includes TENORMINT(atenolol), BREVIBLOC™ (esmolol), NORMODYNE™ (labetalol), TRANDATE™,LOPRESSOR™ (metoprolol), INDERAL™ (propranolol), and BETApp96™(sotalol). Calcium channel blockers includes, for example, NORVASC™(amnlodipine), CARDIZEM™ (diltiazem), PLENDIL™ (felodipine), DYNACRIC™(isradipine), CARDENE™ (nicardipine), ADALAT™ (nifedipine), and CALAN™(verapamil). ACE inhibitors includes, for example, LOTENSIN™(benazepril), CAPOTEN™ (captopril), VASOTEC™ (enalapril), MONOPRIL™(fosinopril), PRINIVIL™ (lisinopril), ACCUPRIL™ (quinapril), and ALTACE™(ramipril). Non-limiting examples of angiotensin II blockers includesAVAPRO™ (irbesartan), COZAAR™ (losartan), and DIOVAN™ (valsartan). Alphaadrenergic blockers includes, for example, CARDURA™ (doxazosin),MINIPRESSm (prazosin), FLOMAX™ (tamsulosin), and terazosin. Hypotensiveagents include, for example, CATAPRES™ (clonidine), APRESOLINE™(hydralazine), ALDOMET™ (methyldopa), LONITEN™ (minoxidil), NIPRIDE™(nitroprusside) and reserpine. Antilipemic agents include, for example,LIPITOR™ (atorvastatin), QUESTRAN™ (cholestyramine), LOLESTID™(colestipol), TRICOR™ (fenofibrate), LOPID™ (gemfibrate), MEVACOR™(lovstatin), PRAVACHOL™ (pravastatin), and ZOCOR™ (simvastatin).Non-limiting examples of vasodilating agents include alprostadil, amylnitrite, PERSANTIN™ (dipyridamole), FLONAN™ (epoprostenol), ISORDIL™(isosorbide dinitrate), IMDUR™ (isosorbide mononitrate), NIMOTOP™(nimodipine), INOmax™ (nitric oxide gas), nitroglycerin, papaverine, andPRISCOLINE™ (tolazoline).

In certain embodiments, Therapeutics of the invention are administeredin combination with antiretroviral agents, nucleoside/nucleotide reversetranscriptase inhibitors (NRTIs), non-nucleoside reverse transcriptaseinhibitors (NNRTIs), and/or protease inhibitors (PIs). NRTIs that may beadministered in combination with the Therapeutics of the invention,include, but are not limited to, RETROVIR™ (zidovudine/AZT), VIDEX™(didanosine/ddI), HIVID™ (zalcitabine/ddC), ZERIT™ (stavudine/d4T),EPIVIR™ (lamivudine/3TC), and COMBIVIR™ (zidovudine/lamivudine). NNRTIsthat may be administered in combination with the Therapeutics of theinvention, include, but are not limited to, VIRAMUN™ (nevirapine),RESCRIPTOR™ (delavirdine), and SUSTIVA™ (efavirenz). Protease inhibitorsthat may be administered in combination with the Therapeutics of theinvention, include, but are not limited to, CRIXIVAN™ (indinavir),NORVIR™ (ritonavir), INVIRASE™ (saquinavir), and VIRACEPT™ (nelfinavir).In a specific embodiment, antiretroviral agents, nucleoside reversetranscriptase inhibitors, non-nucleoside reverse transcriptaseinhibitors, and/or protease inhibitors may be used in any combinationwith Therapeutics of the invention to treat AIDS and/or to prevent ortreat HIV infection.

Additional NRTIs include LODENOSINE™ (F-ddA; an acid-stable adenosineNRTI; Triangle/Abbott; COVIRACIL™ (emtricitabine/FTC; structurallyrelated to lamivudine (3TC) but with 3- to 10-fold greater activity invitro; Triangle/Abbott); dOTC (BCH-10652, also structurally related tolamivudine but retains activity against a substantial proportion oflamivudine-resistant isolates; Biochem Pharma); Adefovir (refusedapproval for anti-HIV therapy by FDA; Gilead Sciences); PREVEON®(Adefovir Dipivoxil, the active prodrug of adefovir; its active form isPMEA-pp); TENOFOVIR™ (bis-POC PMPA, a PMPA prodrug; Gilead); DAPD/DXG(active metabolite of DAPD; Triangle/Abbott); D-D4FC (related to 3TC,with activity against AZT/3TC-resistant virus); GW420867X (GlaxoWellcome); ZIAGEN™ (abacavir/159U89; Glaxo Wellcome Inc.); CS-87(3′azido-2′,3′-dideoxyuridine; WO 99/66936); and S-acyl-2-thioethyl(SATE)-bearing prodrug forms of β-L-FD4C and β-L-FddC (WO 98/17281).

Additional NNRTIs include COACTINON™ (Emivirine/MKC442, potent NNRTI ofthe HEPT class; Triangle/Abbott); CAPRAVRINE™ (AG-1549/S-1153, a nextgeneration NNRTI with activity against viruses containing the K103Nmutation; Agouron); PNU-142721 (has 20- to 50-fold greater activity thanits predecessor delavirdine and is active against K103N mutants;Pharmacia & Upjohn); DPC-961 and DPC-963 (second-generation derivativesof efavirenz, designed to be active against viruses with the K103Nmutation; DuPont); GW-420867X (has 25-fold greater activity than HBY097and is active against K103N mutants; Glaxo Wellcome); CALANOLIDE A(naturally occurring agent from the latex tree; active against virusescontaining either or both the Y181C and K103N mutations); and Propolis(WO 99/49830).

Additional protease inhibitors include LOPINAVIR™ (ABT378/r; AbbottLaboratories); BMS-232632 (an azapeptide; Bristol-Myres Squibb);TIPRANAVIR™ (PNU-140690, a non-peptic dihydropyrone; Pharmacia &Upjohn); PD-178390 (a nonpeptidic dihydropyrone; Parke-Davis); BMS232632 (an azapeptide; Bristol-Myers Squibb); L-756,423 (an indinaviranalog; Merck); DMP-450 (a cyclic urea compound; Avid & DuPont); AG-1776(a peptidonimetic with in vitro activity against proteaseinhibitor-resistant viruses; Agouron); VX-175/GW433908 (phosphateprodrug of amprenavir, Vertex & Glaxo Welcome); CGP61755 (Ciba); andAGENERASE™ (amprenavir; Glaxo Wellcome Inc.).

Additional antiretroviral agents include fusion inhibitors/gp41 binders.Fusion inhibitors/gp41 binders include T-20 (a peptide from residues643-678 of the HIV gp41 transmembrane protein ectodomain which binds togp41 in its resting state and prevents transformation to the fusogenicstate; Trimeris) and T-1249 (a second-generation fusion inhibitor;Trimeris).

Additional antiretroviral agents include fusion inhibitors/chemokinereceptor antagonists. Fusion inhibitors/chemokine receptor antagonistsinclude CXCR4 antagonists such as AMD 3100 (a bicyclam), SDF-1 and itsanalogs, and ALX40-4C (a cationic peptide), T22 (an 18 amino acidpeptide; Trimeris) and the T22 analogs T134 and T140; CCR5 antagonistssuch as RANTES (9-68), AOP-RANTES, NNY-RANTES, and TAK-779; andCCR5/CXCR4 antagonists such as NSC 651016 (a distamycin analog). Alsoincluded are CCR2B, CCR3, and CCR6 antagonists. Chemokine receptoragonists such as RANTES, SDF-1, MIP-1α, MIP-1β, etc., may also inhibitfusion.

Additional antiretroviral agents include integrase inhibitors. Integraseinhibitors include dicaffeoylquinic (DFQA) acids; L-chicoric acid (adicaffeoyltartaric (DCTA) acid); quinalizarin (QLC) and relatedanthraquinones; ZINTEVIR™ (AR 177, an oligonucleotide that probably actsat cell surface rather than being a true integrase inhibitor; Arondex);and naphthols such as those disclosed in WO 98/50347.

Additional antiretroviral agents include hydroxyurea-like compounds suchas BCX-34 (a purine nucleoside phosphorylase inhibitor; Biocryst);ribonucleotide reductase inhibitors such as DIDOX™ (Molecules forHealth); inosine monophosphate dehydrogenase (IMPDH) inhibitors sucha asVX-497 (Vertex); and mycopholic acids such as CellCept (mycophenolatemofetil; Roche).

Additional antiretroviral agents include inhibitors of viral integrase,inhibitors of viral genome nuclear translocation such as arylenebis(methylketone) compounds; inhibitors of H1V entry such as AOP-RANTES,NNY-RANTES, RANTES-IgG fusion protein, soluble complexes of RANTES andglycosaminoglycans (GAG), and AMD-3100; nucleocapsid zinc fingerinhibitors such as dithiane compounds; targets of HIV Tat and Rev; andpharmacoenhancers such as ABT-378.

Other antiretroviral therapies and adjunct therapies include cytokinesand lymphokines such as MIP-1α, MIP-1β, SDF-1α, IL-2, PROLEUKIN™(aldesleukin/L2-7001; Chiron), IL-4, IL-10, IL-12, and IL-13;interferons such as IFN-α2a; antagonists of TNFs, NFκB, GM-CSF, M-CSF,and IL-10; agents that modulate immune activation such as cyclosporinand prednisone; vaccines such as Remune™ (HIV Immunogen), APL 400-003(Apollon), recombinant gp120 and fragments, bivalent (B/E) recombinantenvelope glycoprotein, rgp120CM235, MN rgp120, SF-2 rgp120,gp120/soluble CD4 complex, Delta JR-FL protein, branched syntheticpeptide derived from discontinuous gp120 C31C4 domain, fusion-competentimmunogens, and Gag, Pol, Nef, and Tat vaccines; gene-based therapiessuch as genetic suppressor elements (GSEs; WO 98/54366), and intralines(genetically modified CC chemokines targetted to the ER to block surfaceexpression of newly synthesized CCR5 (Yang et al., PNAS 94:11567-72(1997); Chen et al., Nat. Med. 3:1110-16 (1997)); antibodies such as theanti-CXCR4 antibody 12G5, the anti-CCR5 antibodies 2D7, 5C7, PA8, PA9,PA10, PA11, PA12, and PA14, the anti-CD4 antibodies Q4120 and RPA-T4,the anti-CCR3 antibody 7B11, the anti-gp120 antibodies 17b, 48d,447-52D, 257-D, 268-D and 50.1, anti-Tat antibodies, anti-TNF-αantibodies, and monoclonal antibody 33A; aryl hydrocarbon (AH) receptoragonists and antagonists such as TCDD, 3,3′,4,4′,5-pentachlorobiphenyl,3,3′,4,4′-tetrachlorobiphenyl, and α-naphthoflavone (WO 98/30213); andantioxidants such as γ-L-glutamyl-L-cysteine ethyl ester (γ-GCE; WO99/56764).

In a further embodiment, the Therapeutics of the invention areadministered in combination with an antiviral agent. Antiviral agentsthat may be administered with the Therapeutics of the invention include,but are not limited to, acyclovir, ribavirin, amantadine, andremantidine.

In other embodiments, Therapeutics of the invention may be administeredin combination with anti-opportunistic infection agents.Anti-opportunistic agents that may be administered in combination withthe Therapeutics of the invention, include, but are not limited to,TRIMETHOPRIM-SULFAMETHOXAZOLE™, DAPSONE™, PENTAMINE™, ATOVAQUONE™,ISONIAZID™, RIFAMPIN™, PYRAZINAMIDE™, ETHAMBUTOL™, RIFABUTIN™,CLARITROMYCIN™, AZITHROMYCIN™, GANCICLOVIR™, FOSCARNET™, CIDOFOVIR™,FLUCONAZOLE™, ITRACONAZOLE™, KETOCONAZOLE™, ACYCLOVIR™, FAMCICOLVIR™,PYRIMETHAMINE™, LEUCOVORINM, NEUPOGEN™ (filgrastim/G-CSF), and LEUKINE™(sargramostim/GM-CSF). In a specific embodiment, Therapeutics of theinvention are used in any combination withTRIMETHOPRIMSULFAMETHOXAZOLE™, DAPSONE™, PENTAMDINE™, and/or ATOVAQUONE™to prophylactically treat or prevent an opportunistic Pneumocystiscarinii pneumonia infection. In another specific embodiment,Therapeutics of the invention are used in any combination withISONIAZID™, RIFAMPIN™, PYRAZINAMIDE™, and/or ETHAMBUTOL™ toprophylactically treat or prevent an opportunistic Mycobacterium aviumcomplex infection. In another specific embodiment, Therapeutics of theinvention are used in any combination with RIFABUTIN™, CLARITHROMYCIN™,and/or AZNMOMYCIN™ to prophylactically treat or prevent an opportunisticMycobacterium tuberculosis infection. In another specific embodiment,Therapeutics of the invention are used in any combination withGANCICLOVIR™, FOSCARNET™, and/or CIDOFOVIR™ to prophylactically treat orprevent an opportunistic cytomegalovirus infection. In another specificembodiment, Therapeutics of the invention are used in any combinationwith FLUCONAZOLE™, ITRACONAZOLE™, and/or KETOCONAZOLE™ toprophylactically treat or prevent an opportunistic fungal infection. Inanother specific embodiment, Therapeutics of the invention are used inany combination with ACYCLOVIR™ and/or FAMCICOLVIR™ to prophylacticallytreat or prevent an opportunistic herpes simplex virus type I and/ortype II infection. In another specific embodiment, Therapeutics of theinvention are used in any combination with PYRIMETHAMINE™ and/orLEUCOVORIN™ to prophylactically treat or prevent an opportunisticToxoplasma gondii infection. In another specific embodiment,Therapeutics of the invention are used in any combination withLEUCOVORIN™ and/or NEUPOGEN™ to prophylactically treat or prevent anopportunistic bacterial infection.

In a further embodiment, the Therapeutics of the invention areadministered in combination with an antibiotic agent. Antibiotic agentsthat may be administered with the Therapeutics of the invention include,but are not limited to, amoxicillin, beta-lactamases, aminoglycosides,beta-lactam (glycopeptide), beta-lactamases, Clindamycin,chloramphenicol, cephalosporins, ciprofioxacin, erythromycin,fluoroquinolones, macrolides, metronidazole, penicillins, quinolones,rapamycin, rifampin, streptomycin, sulfonamide, tetracyclines,trimethoprim, trimethoprim-sulfamethoxazole, and vancomycin.

In other embodiments, the Therapeutics of the invention are administeredin combination with immunestimulants. Immunostimulants that may beadministered in combination with the Therapeutics of the inventioninclude, but are not limited to, levamisole (e.g., ERGAMISOL™),isoprinosine (e.g. INOSIPLEX™), interferons (e.g. interferon alpha), andinterleutins (e.g., EL-2).

In other embodiments, Therapeutics of the invention are administered incombination with immunosuppressive agents. Immunosuppressive agents thatmay be administered in combination with the Therapeutics of theinvention include, but are not limited to, steroids, cyclosporine,cyclosporine analogs, cyclophosphamide methylprednisone, prednisone,azathioprine, FK-506, 15-deoxyspergualin, and other immunosuppressiveagents that act by suppressing the function of responding T cells. Otherimmunosuppressive agents that may be administered in combination withthe Therapeutics of the invention include, but are not limited to,prednisolone, methotrexate, thalidomide, methoxsalen, rapamycin,leflunomide, mizoribine (BREDININ™), brequinar, deoxyspergualin, andazaspirane (SKF 105685), ORTHOCLONE OKT® 3 (muromonab-CD3), SANDIMMUNE™,NEORAL™, SANGDYA™ (cyclosporine), PROGRAF® (FK506, tacrolimus),CELLCEPT® (mycophenolate motefil, of which the active metabolite ismycophenolic acid), IMURAN™ (azathioprine), glucocorticosteroids,adrenocortical steroids such as DELTASONET (prednisone) and HYDELTRASOL™(prednisolone), FOLEX™ and MEXATE™ (methotrxate), OXSORALEN-ULTRA™(methoxsalen) and RAPAMUNE™ (sirolimus). In a specific embodiment,immunosuppressants may be used to prevent rejection of organ or bonemarrow transplantation.

In an additional embodiment, Therapeutics of the invention areadministered alone or in combination with one or more intravenous immuneglobulin preparations. Intravenous immune globulin preparations that maybe administered with the Therapeutics of the invention include, but notlimited to, GAMMAR™, IVEEGAM™, SANDOGLOBULIN™, GAMMAGARD S/D™,ATGAM™(antithymocyte glubulin), and GAMIMUNE™. In a specific embodiment,Therapeutics of the invention are administered in combination withintravenous immune globulin preparations in transplantation therapy(e.g., bone marrow transplant).

In certain embodiments, the Therapeutics of the invention areadministered alone or in combination with an anti-inflammatory agent.Anti-inflammatory agents that may be administered with the Therapeuticsof the invention include, but are not limited to, corticosteroids (e.g.betamethasone, budesonide, cortisone, dexamethasone, hydrocortisone,methylprednisolone, prednisolone, prednisone, and triamcinolone),nonsteroidal anti-inflammatory drugs (e.g., diclofenac, diflunisal,etodolac, fenoprofen, floctafenine, flurbiprofen, ibuprofen,indomethacin, ketoprofen, meclofenamate, mefenamic acid, meloxicam,nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam, sulindac,tenoxicam, tiaprofenic acid, and tolmetin.), as well as antihistamines,aminoarylcarboxylic acid derivatives, arylacetic acid derivatives,arylbutyric acid derivatives, arylcarboxylic acids, arylpropionic acidderivatives, pyrazoles, pyrazolones, salicylic acid derivatives,thiazinecarboxamides, e-acetamidocaproic acid, S-adenosylmethionine,3-amino-4-hydroxybutyric acid, amixetrine, bendazac, benzydamine,bucolome, difenpiramide, ditazol, emorfazone, guaiazulene, nabumetone,nimesulide, orgotein, oxaceprol, paranyline, perisoxal, pifoxime,proquazone, proxazole, and tenidap.

In an additional embodiment, the compositions of the invention areadministered alone or in combination with an anti-angiogenic agent.Anti-angiogenic agents that may be administered with the compositions ofthe invention include, but are not limited to, Angiostatin (Entremed,Rockville, Md.), Troponin-1 (Boston Life Sciences, Boston, Mass.),anti-Invasive Factor, retinoic acid and derivatives thereof, paclitaxel(Taxol), Suramin, Tissue Inhibitor of Metalloproteinase-1, TissueInhibitor of Metalloproteinase-2, VEGI, Plasminogen ActivatorInhibitor-1, Plasminogen Activator Inhibitor-2, and various forms of thelighter “d group” transition metals.

Lighter “d group” transition metals include, for example, vanadium,molybdenum, tungsten, titanium, niobium, and tantalum species. Suchtransition metal species may form transition metal complexes. Suitablecomplexes of the above-mentioned transition metal species include oxotransition metal complexes.

Representative examples of vanadium complexes include oxo vanadiumcomplexes such as vanadate and vanadyl complexes. Suitable vanadatecomplexes include metavanadate and orthovanadate complexes such as, forexample, ammonium metavanadate, sodium metavanadate, and sodiumorthovanadate. Suitable vanadyl complexes include, for example, vanadylacetylacetonate and vanadyl sulfate including vanadyl sulfate hydratessuch as vanadyl sulfate mono- and trihydrates.

Representative examples of tungsten and molybdenum complexes alsoinclude oxo complexes. Suitable oxo tungsten complexes include tungstateand tungsten oxide complexes. Suitable tungstate complexes includeammonium tungstate, calcium tungstate, sodium tungstate dihydrate, andtungstic acid. Suitable tungsten oxides include tungsten (I) oxide andtungsten (VI) oxide. Suitable oxo molybdenum complexes includemolybdate, molybdenum oxide, and molybdenyl complexes. Suitablemolybdate complexes include ammonium molybdate and its hydrates, sodiummolybdate and its hydrates, and potassium molybdate and its hydrates.Suitable molybdenum oxides include molybdenum (VI) oxide, molybdenum(VI) oxide, and molybdic acid. Suitable molybdenyl complexes include,for example, molybdenyl acetylacetonate. Other suitable tungsten andmolybdenum complexes include hydroxo derivatives derived from, forexample, glycerol, tartaric acid, and sugars.

A wide variety of other anti-angiogenic factors may also be utilizedwithin the context of the present invention. Representative examplesinclude, but are not limited to, platelet factor 4; protamine sulphate;sulphated chitin derivatives (prepared from queen crab shells), (Murataet al., Cancer Res. 51:22-26, (1991)); Sulphated PolysaccharidePeptidoglycan Complex (SP-PG) (the function of this compound may beenhanced by the presence of steroids such as estrogen, and tamoxifencitrate); Staurosporine; modulators of matrix metabolism, including forexample, proline analogs, cishydroxyproline, d,L-3,4-dehydroproline,Thiaproline, alpha,alpha-dipyridyl, aminopropionitrile furate;4-propyl-54-pyridinyl)-2(3H)-oxazolone; Methotrexate; Mitoxantrone;Heparin; Interferons; 2 Macroglobulin-serum; ChIMP-3 (Pavloff et al., J.Bio. Chem. 267:17321-17326, (1992)); Chymostatin (Tomkinson et al.,Biochem J. 286:475480, (1992)); Cyclodextrin Tetradecasulfate;Eponemycin; Camptothecin; Fumagillin (Ingber et al., Nature 348:555-557,(1990)); Gold Sodium Thiomalate (“GST”; Matsubara and Ziff, J. Clin.Invest. 79:1440-1446, (1987)); anticollagenase-serum; alpha2-antiplasmin(Holmes et al., J. Biol. Chem. 262(4):1659-1664, (1987)); Bisantrene(National Cancer Institute); Lobenzarit disodium(N2)-carboxyphenyl-4-chloroanthronilic acid disodium or “CCA”; (Takeuchiet al., Agents Actions 36:312-316, (1992)); and metalloproteinaseinhibitors such as BB94.

Additional anti-angiogenic factors that may also be utilized within thecontext of the present invention include Thalidomide, (Celgene, Warren,N.J.); Angiostatic steroid; AGM-1470 (H. Brem and J. Folkman J Pediatr.Surg. 28:445-51 (1993)); an integrin alpha v beta 3 antagonist (C.Storgard et al., J Clint. Invest. 103:47-54 (1999));carboxynaminolmidazole; Carboxyanidotriazole (CAI) (National CancerInstitute, Bethesda, Md.); Conbretastatin A-4 (CA4P) (OXiGENE, Boston,Mass.); Squalamine (Magainin Pharmaceuticals, Plymouth Meeting, Pa.);TNP470, (Tap Pharmaceuticals, Deerfield, Ill.); ZD-0101 AstraZeneca(London, UK); APRA (CT2584); Benefin, Byrostatin-1 (SC339555); CGP41251(PKC 412); CM101; Dexrazoxane (ICRF187); DMXAA; Endostatin;Flavopridiol; Genestein; GTE; ImmTher; Iressa (ZD1839); Octreotide(Somatostatin); Panretin; Penacillamine; Photopoint; PI-88; Prinomastat(AG-3340) Purlytin; Suradista (FCE26644); Tamoxifen (Nolvadex);Tazarotene; Tetrathiomolybdate; Xeloda (Capecitabine); and5-Fluorouracil.

Anti-angiogenic agents that may be administed in combination with thecompounds of the invention may work through a variety of mechanismsincluding, but not limited to, inhibiting proteolysis of theextracellular matrix, blocking the function of endothelialcell-extracellular matrix adhesion molecules, by antagonizing thefunction of angiogenesis inducers such as growth factors, and inhibitingintegrin receptors expressed on proliferating endothelial cells.Examples of anti-angiogenic inhibitors that interfere with extracellularmatrix proteolysis and which may be administered in combination with thecompositons of the invention include, but are not limited to, AG-3340(Agouron, La Jolla, Calif.), BAY-12-9566 (Bayer, West Haven, Conn.),BMS-275291 (Bristol Myers Squibb, Princeton, N.J.), CGS-27032A(Novartis, East Hanover, N.J.), Marimastat (British Biotech, Oxford,UK), and Metastat (Aeterna, St-Foy, Quebec). Examples of anti-angiogenicinhibitors that act by blocking the function of endothelialcell-extracellular matrix adhesion molecules and which may beadministered in combination with the compositons of the inventioninclude, but are not limited to, EMD-121974 (Merck KcgaA Darmstadt,Germany) and Vitaxin (Ixsys, La Jolla, Calif./Medimmune, Gaithersburg,Md.). Examples of anti-angiogenic agents that act by directlyantagonizing or inhibiting angiogenesis inducers and which may beadministered in combination with the compositons of the inventioninclude, but are not limited to, Angiozyme (Ribozyme, Boulder, Colo.),Anti-VEGF antibody (Genentech, S. San Francisco, Calif.),PTK-787/ZK-225846 (Novartis, Basel, Switzerland), SU-101 (Sugen, S. SanFrancisco, Calif.), SU-5416 (Sugen/Pharmacia Upjohn, Bridgewater, N.J.),and SU-6668 (Sugen). Other anti-angiogenic agents act to indirectlyinhibit angiogenesis. Examples of indirect inhibitors of angiogenesiswhich may be administered in combination with the compositons of theinvention include, but are not limited to, IM-862 (Cytran, Kirkland,Wash.), Interferon-alpha, IL-12 (Roche, Nutley, N.J.), and Pentosanpolysulfate (Georgetown University, Washington, D.C.).

In particular embodiments, the use of compositions of the invention incombination with anti-angiogenic agents is contemplated for thetreatment, prevention, and/or amelioration of an autoimmune disease,such as for example, an autoimmune disease described herein.

In a particular embodiment, the use of compositions of the invention incombination with anti-angiogenic agents is contemplated for thetreatment, prevention, and/or amelioration of arthritis. In a moreparticular embodiment, the use of compositions of the invention incombination with anti-angiogenic agents is contemplated for thetreatment, prevention, and/or amelioration of rheumatoid arthritis.

In another embodiment, the polynucleotides encoding a polypeptide of thepresent invention are administered in combination with an angiogenicprotein, or polynucleotides encoding an angiogenic protein. Examples ofangiogenic proteins that may be administered with the compositions ofthe invention include, but are not limited to, acidic and basicfibroblast growth factors, VEGF-1, VEGF-2, VEGF-3, epidermal growthfactor alpha and beta, platelet-derived endothelial cell growth factor,platelet-derived growth factor, tumor necrosis factor alpha, hepatocytegrowth factor, insulin-like growth factor, colony stimulating factor,macrophage colony stimulating factor, granulocyte/macrophage colonystimulating factor, and nitric oxide synthase.

In additional embodiments, compositions of the invention areadministered in combination with a chemotherapeutic agent.Chemotherapeutic agents that may be administered with the Therapeuticsof the invention include, but are not limited to alkylating agents suchas nitrogen mustards (for example, Mechlorethamine, cyclophosphamide,Cyclophosphamide Ifosfamide, Melphalan (L-sarcolysin), andChlorambucil), ethyleninines and methylmelamines (for example,Hexamethylmelamine and Thiotepa), alkyl sulfonates (for example,Busulfan), nitrosoureas (for example, Carmustine (BCNU), Lomustine(CCNU), Semustine (methyl-CCNU), and Streptozocin (streptozotocin)),triazenes (for example, Dacarbazine (DTIC;dimethyltriazenoimidazolecarboxamide)), folic acid analogs (for example,Methotrexate (amethopterin)), pyrimidine analogs (for example,Fluorouacil (5-fluorouracil; 5-FU), Floxuridine (fluorodeoxyuridine;FudR), and Cytarabine (cytosine arabinoside)), purine analogs andrelated inhibitors (for example, Mercaptopurine (6-mercaptopurine;6-MP), Thioguanine (6-thioguanine; TG), and Pentostatin(2′-deoxycoformycin)), vinca alkaloids (for example, Vinblastine (VLB,vinblastine sulfate)) and Vincristine (vincristine sulfate)),epipodophyllotoxins (for example, Etoposide and Teniposide), antibiotics(for example, Dactinomycin (actinomycin D), Daunorubicin (daunomycin;rubidomycin), Doxorubicin, Bleomycin, Plicamycin (mithramycin), andMitomycin (mitomycin C), enzymes (for example, L-Asparaginase),biological response modifiers (for example, Interferon-alpha andinterferon-alpha-2b), platinum coordination compounds (for example,Cisplatin (cis-DDP) and Carboplatin), anthracenedione (Mitoxantrone),substituted ureas (for example, Hydroxyurea), methylhydrazinederivatives (for example, Procarbazine (N-methylhydrazine; MIH),adrenocorticosteroids (for example, Prednisone), progestins (forexample, Hydroxyprogesterone caproate, Medroxyprogesterone,Medroxyprogesterone acetate, and Megestrol acetate), estrogens (forexample, Diethylstilbestrol (DES), Diethylstilbestrol diphosphate,Estradiol, and Ethinyl estradiol), antiestrogens (for example,Tamoxifen), androgens (Testosterone proprionate, and Fluoxymesterone),antiandrogens (for example, Flutamide), gonadotropin-releasing horomoneanalogs (for example, Leuprolide), other hormones and hormone analogs(for example, methyltestosterone, estramustine, estramustine phosphatesodium, chlorotrianisene, and testolactone), and others (for example,dicarbazine, glutamic acid, and mitotane).

In one embodiment, the compositions of the invention are administered incombination with one or more of the following drugs: inflimab (alsoknown as Remicade™ Centocor, Inc.), Trocade (Roche, RO-32-3555),Leflunomide (also known as Arava™ from Hoechst Marion Roussel), Kineret™(an IL-1 Receptor antagonist also known as Anakinra from Amgen, Inc.)

In a specific embodiment, compositions of the invention are administeredin combination with CHOP (cyclophosphamide, doxorubicin, vincristine,and prednisone) or combination of one or more of the components of CHOP.In one embodiment, the compositions of the invention are administered incombination with anti-CD20 antibodies, human monoclonal anti-CD20antibodies. In another embodiment, the compositions of the invention areadministered in combination with anti-CD20 antibodies and CHOP, oranti-CD20 antibodies and any combination of one or more of thecomponents of CHOP, particularly cyclophosphamide and/or prednisone. Ina specific embodiment, compositions of the invention are administered incombination with Rituximab. In a further embodiment, compositions of theinvention are administered with Rituximab and CHOP, or Rituximab and anycombination of one or more of the components of CHOP, particularlycyclophosphamide and/or prednisone. In a specific embodiment,compositions of the invention are administered in combination withtositumomab. In a further embodiment, compositions of the invention areadministered with tositumomab and CHOP, or tositumomab and anycombination of one or more of the components of CHOP, particularlycyclophosphamide and/or prednisone. The anti-CD20 antibodies mayoptionally be associated with radioisotopes, toxins or cytotoxicprodrugs.

In another specific embodiment, the compositions of the invention areadministered in combination Zevalin™. In a further embodiment,compositions of the invention are administered with Zevalin™ and CHOP,or Zevalin™ and any combination of one or more of the components ofCHOP, particularly cyclophosphamide and/or prednisone. Zevalin™ may beassociated with one or more radisotopes. Particularly preferred isotopesare ⁹⁰Y and ¹¹¹In.

In an additional embodiment, the Therapeutics of the invention areadministered in combination with cytokines. Cytokines that may beadministered with the Therapeutics of the invention include, but are notlimited to, IL2, IL3, IL4, IL5, IL6, IL7, IL10, IL12, IL13, IL15,anti-CD40, CD40L, IFN-gamma and TNF-alpha. In another embodiment,Therapeutics of the invention may be administered with any interleukin,including, but not limited to, IL-1alpha, IL-1beta, IL-2, IL-3, IL4,IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-li, IL-12, IL-13, IL-14, IL-15,IL-16, IL-17, IL-18, IL-19, IL-20, and IL-21.

In one embodiment, the Therapeutics of the invention are administered incombination with members of the TNF family. TNF, TNF-related or TNF-likemolecules that may be administered with the Therapeutics of theinvention include, but are not limited to, soluble forms of TNF-alpha,lymphotoxin-alpha (LT-alpha, also known as TNF-beta), LT-beta (found incomplex heterotrimer LT-alpha2-beta), OPGL, FasL, CD27L, CD30L, CD40L,4-1BBL, DcR3, OX40L, TNP-gamma (International Publication No. WO96/14328), AIM-I (International Publication No. WO 97/33899),endokine-alpha (International Publication No. WO 98/07880), OPG, andneutrokine-alpha (International Publication No. WO 98/18921, OX40, andnerve growth factor (NGF), and soluble forms of Fas, CD30, CD27, CD40and 4-IBB, TR2 (International Publication No. WO 96/34095), DR3(International Publication No. WO 97/33904), DR4 (InternationalPublication No. WO 98/32856), TR5 (International Publication No. WO98/30693), TRANK, TR9 (International Publication No. WO 98/56892),TR10(International Publication No. WO 98/54202), 312C2 (InternationalPublication No. WO 98/06842), and TR12, and soluble forms CD154, CD70,and CD153.

In an additional embodiment, the Therapeutics of the invention areadministered in combination with angiogenic proteins. Angiogenicproteins that may be administered with the Therapeutics of the inventioninclude, but are not limited to, Glioma Derived Growth Factor (GDGF), asdisclosed in European Patent Number EP-399816; Platelet Derived GrowthFactor-A (PDGF-A), as disclosed in European Patent Number EP-682110;Platelet Derived Growth Factor-B (PDGF-B), as disclosed in EuropeanPatent Number EP-282317; Placental Growth Factor (P1GF), as disclosed inInternational Publication Number WO 92/06194; Placental Growth Factor-2(P1GF-2), as disclosed in Hauser et al., Growth Factors, 4:259-268(1993); Vascular Endothelial Growth Factor (VEGF), as disclosed inInternational Publication Number WO 90/13649; Vascular EndothelialGrowth Factor-A (VEGF-A), as disclosed in European Patent NumberEP-506477; Vascular Endothelial Growth Factor-2 (VEGF-2), as disclosedin International Publication Number WO 96/39515; Vascular EndothelialGrowth Factor B (VEGF-3); Vascular Endothelial Growth Factor B-186(VEGF-B186), as disclosed in International Publication Number WO96/26736; Vascular Endothelial Growth Factor-D (VEGF-D), as disclosed inInternational Publication Number WO 98/02543; Vascular EndothelialGrowth Factor-D (VEGF-D), as disclosed in International PublicationNumber WO 98/07832; and Vascular Endothelial Growth Factor-E (VEGF-E),as disclosed in German Patent Number DE19639601. The above mentionedreferences are herein incorporated by reference in their entireties.

In an additional embodiment, the Therapeutics of the invention areadministered in combination with Fibroblast Growth Factors. FibroblastGrowth Factors that may be administered with the Therapeutics of theinvention include, but are not limited to, FGF-1, FGF-2, FGF-3, FGF-4,FGF-5, FGF-6, FGF-7, FGF-8, FGF-9, FGF-10, FGF-11, FGF-12, FGF-13,FGF-14, and FGF-15.

In an additional embodiment, the Therapeutics of the invention areadministered in combination with hematopoietic growth factors.Hematopoietic growth factors that may be administered with theTherapeutics of the invention include, but are not limited to,granulocyte macrophage colony stimulating factor (GM-CSF) (sargramostim,LEUKINE™, PROKINE™), granulocyte colony stimulating factor (G-CSF)(filgrastim, NEUPOGEN™), macrophage colony stimulating factor (M-CSF,CSF-1) erythropoietin (epoetin alfa, EPOGEN™, PROCRIT™), stem cellfactor (SCF, c-kit ligand, steel factor), megakaryocyte colonystimulating factor, PIXY321 (a GMCSF/IL-3 fusion protein), interleukins,especially any one or more of IL-1 through IL-12, interferon-gamma, orthrombopoietin.

In certain embodiments, Therapeutics of the present invention areadministered in combination with adrenergic blockers, such as, forexample, acebutolol, atenolol, betaxolol, bisoprolol, carteolol,labetalol, metoprolol, nadolol, oxprenolol, penbutolol, pindolol,propranolol, sotalol, and timolol.

In another embodiment, the Therapeutics of the invention areadministered in combination with an antiarrhythmic drug (e.g.,adenosine, amidoarone, bretylium, digitalis, digoxin, digitoxin,diliazem, disopyramide, esmolol, flecainide, lidocaine, mexiletine,moricizine, phenyloin, procainamide, N-acetyl procainamide, propafenone,propranolol, quinidine, sotalol, tocainide, and verapamil).

In another embodiment, the Therapeutics of the invention areadministered in combination with diuretic agents, such as carbonicanhydrase-inhibiting agents (e.g., acetazolamide, dichlorphenamide, andmethazolamide), osmotic diuretics (e.g., glycerin, isosorbide, mannitol,and urea), diuretics that inhibit Na⁺-K⁺-2Cl⁻ symport (e.g., furosemide,bumetanide, azosemide, piretanide, tripamide, ethacrynic acid,muzolimine, and torsemide), thiazide and thiazide-like diuretics (e.g.,bendroflumethiazide, benzthiazide, chlorothiazide, hydrochlorothiazide,hydroflumethiazide, methyclothiazide, polythiazide, trichormethiazide,chlorthalidone, indapamide, metolazone, and quinethazone), potassiumsparing diuretics (e.g., amiloride and triamterene), andmineralcorticoid receptor antagonists (e.g., spironolactone, canrenone,and potassium canrenoate).

In one embodiment, the Therapeutics of the invention are administered incombination with treatments for endocrine and/or hormone imbalancedisorders. Treatments for endocrine and/or hormone imbalance disordersinclude, but are not limited to, ¹²⁷I, radioactive isotopes of iodinesuch as ¹³¹I and ¹²³I; recombinant growth hormone, such as HUMATROPE™(recombinant somatropin); growth hormone analogs such as PROTROPIN™(somatrem); dopamine agonists such as PARLODEL™ (bromocriptine);somatostatin analogs such as SANDOSTATIN™ (octreotide); gonadotropinpreparations such as PREGNYL™, A.P.L.™ and PROFASI™ (chorionicgonadotropin (CG)), PERGONAL™ (menotropins), and METRODIN™(urofollitropin (uFSH)); synthetic human gonadotropin releasing hormonepreparations such as FACTREL™ and LUTREPULSE™ (gonadorelinhydrochloride); synthetic gonadotropin agonists such as LUPRON™(leuprolide acetate), SUPPRELIN™ (histrelin acetate), SYNAREL™(nafarelin acetate), and ZOLADEX™ (goserelin acetate); syntheticpreparations of thyrotropin-releasing hormone such as RELEFACT TRH™ andTHYPINONE™ (protirelin); recombinant human TSH such as THYROGEN™;synthetic preparations of the sodium salts of the natural isomers ofthyroid hormones such as L-T₄™, SYNTHROID™ and LEVOTHROID™(levothyroxine sodium), L-T₃™, CYTOMEL™ and TRIOSTAT™ (liothyroinesodium), and THYROLAR™ (liotrix); antithyroid compounds such as6-n-propylthiouracil (propylthiouracil), 1-methyl-2-mercaptoimidazoleand TAPAZOLE™ (methimazole), NEO-MERCAZOLE™ (carbimazole);beta-adrenergic receptor antagonists such as propranolol and esmolol;Ca²⁺ channel blockers; dexamethasone and iodinated radiological contrastagents such as TELEPAQUE™ (iopanoic acid) and ORAGRAFIN™ (sodiumipodate).

Additional treatments for endocrine and/or hormone imbalance disordersinclude, but are not limited to, estrogens or congugated estrogens suchas ESTRACE™ (estradiol), ESTINYL™ (ethinyl estradiol), PREMARIN™,ESTRATAB™, ORTHO-EST™, OGEN™ and estropipate (estrone), ESTROVIS™(quinestrol), ESTRADERM™ (estradiol), DELESTROGEN™ and VALERGEN™(estradiol valerate), DEPO-ESTRADIOL CYPIONATE™ and ESTROJECT LA™(estradiol cypionate); antiestrogens such as NOLVADEX™ (tamnoxifen),SEROPHBENE™ and CLOMID™ (clomiphene); progestins such as DURALUTIN™(hydroxyprogesterone caproate), MPA™ and DEPO-PROVERA™(medroxyprogesterone acetate), PROVERA™ and CYCRIN™ (MPA), MEGACE™(megestrol acetate), NORLUTIN™ (norethindrone), and NORLUTATE™ andAYGESTIN™ (norethindrone acetate); progesterone implants such asNORPLANT SYSTEM™ (subdermal implants of norgestrel); antiprogestins suchas RU 486™ (mifepristone); hormonal contraceptives such as ENOVID™(norethynodrel plus mestranol), PROGESTASERT™ (intrauterine device thatreleases progesterone), LOESTRIN™, BREVICON™, MODICON™, GENORA™,NELONA™, NORINYL™, OVACON-35™ and OVACON-50™ (ethinylestradiol/norethindrone), LEVLEN™, NORDETTE™, TR1-LEVLEN™ andTRIPHASIL-21™ (ethinyl estradiol/levonorgestrel) LO/OVRAL™ and OVRAL™(ethinyl estradiol/norgestrel), DEMULEN™ (ethinyl estradiol/ethynodioldiacetate), NORINYL™, ORTHO-NOVUM™, NORETHIN™, GENORA™, and NELOVA™(norethindrone/mestranol), DESOGEN™ and ORTHO-CEPT™ (ethinylestradiol/desogestrel), ORTHO-CYCLEN™ and ORTHO-TRICYCLEN™ (ethinylestradiol/norgestimate), MICRONOR™ and NOR-QD™ (norethindrone), andOVRETTE™ (norgestrel).

Additional treatments for endocrine and/or hormone imbalance disordersinclude, but are not limited to, testosterone esters such as methenoloneacetate and testosterone undecanoate; parenteral and oral androgens suchas TESTOJECT-50™ (testosterone), TESTEX™ (testosterone propionate),DELATESTRYL™ (testosterone enanthate), DEPO-TESTOSTERONE™ (testosteronecypionate), DANOCRINE™ (danazol), HALOTESTIN™ (fluoxymesterone), ORETONMETHYL™, TESTRED™ and VIRILON™ (methyltestosterone), and OXANDRIN™(oxandrolone); testosterone transdermal systems such as TESTODERM™;androgen receptor antagonist and 5-alpha-reductase inhibitors such asANDROCUR™ (cyproterone acetate), EULEXIN™ (flutamide), and PROSCAR™(finasteride); adrenocorticotropic hormone preparations such asCORTROSYN™ (cosyntropin); adrenocortical steroids and their syntheticanalogs such as ACLOVATE™ (alclometasone dipropionate), CYCLOCORT™(amcinonide), BECLOVENT™ and VANCERIL™ (beclomethasone dipropionate),CELESTONE™ (betamethasone), BENISONE™ and UTICORT™ (betamethasonebenzoate), DIPROSONE™ (betamethasone dipropionate), CELESTONE PHOSPHATE™(betamethasone sodium phosphate), CELESTONE SOLUSPAN™ (betamethasonesodium phosphate and acetate), BETA-VAL™ and VALISONET (betamethasonevalerate), TEMOVATE™ (clobetasol propionate), CLODERM™ (clocortolonepivalate), CORTIF™ and HYDROCORTONE™ (cortisol (hydrocortisone)),HYDROCORTONE ACETATE™ (cortisol (hydrocortisone)acetate), LOCOD™(cortisol (hydrocortisone)butyrate), HYDROCORTONE PHOSPHATE™ (cortisol(hydrocortisone) sodium phosphate), A-HYDROCORT™ and SOLU CORTEF™(cortisol (hydrocortisone) sodium succinate), WESTCORT™ (cortisol(hydrocortisone) valerate), CORTISONE ACETATE™ (cortisone acetate),DESOWEN™ and TRIDESILONT” (desonide), TOPICORT™ (desoximetasone),DECADRON™ (dexamethasone), DECADRON LA™ (dexamethasone acetate),DECADRON PHOSPHATE™ and HEXADROL PHOSPHATE™ (dexamethasone sodiumphosphate), FLORONE™ and MAXILOR™ (diflorasone diacetate), FLORINEFACETATE™ (fludrocortisone acetate), AEROBID™ and NASALIDE™(flunisolide), FLUONID™ and SYNALAR™ (fluocinolone acetonide), LIDEX™(fluocinonide), FLUOR-OP™ and FML™ (fluorometholone), CORDRAN™(flurandrenolide), HALOG™ (halcinonide), HMS LIZUIFILM™ (medrysone),MEDROL™ (methylprednisolone), DEPO-MEDROL™ and MEDROL ACETATE™(methylprednisone acetate), A-METHAPRED™ and SOLUMEDROL™(methylprednisolone sodium succinate), ELOCON™ (mometasone furoate),HALDRONE™ (paramethasone acetate), DELTA-CORTEF™ (prednisolone),ECONOPRED™ (prednisolone acetate), HYDELTRASOL™ (prednisolone sodiumphosphate), HYDELTRA-T.B.A™ (prednisolone tebutate), DELTASONE™(prednisone), ARISTOCORT™ and KENACORT™ (triamcinolone), KENALOG™(triamcinolone acetonide), ARISTOCORT™ and KENACORT DIACETATE™(triamcinolone diacetate), and ARISTOSPAN™ (triamcinolone hexacetonide);inhibitors of biosynthesis and action of adrenocortical steroids such asCYTADREN™ (aminoglutethimide), NIZORAL™ (ketoconazole), MODRASTANE™(trilostane), and METOPIRONE™ (metyrapone); bovine, porcine or humaninsulin or mixtures thereof; insulin analogs; recombinant human insulinsuch as HUMULIN™ and NOVOLIN™; oral hypoglycemic agents such as ORAMIDE™and ORINASE™ (tolbutamide), DIABINESE™ (chlorpropamide), TOLAMIDE™ andTOLINASE™ (tolazamide), DYMBLOR™ (acetohexamide), glibenclamide,MICRONASE™, DIBETA™ and GLYNASE™ (glyburide), GLUCOTROL™ (glipizide),and DIAMICRON™ (gliclazide), GLUCOPHAGE™ (metformin), ciglitazone,pioglitazone, and alpha-glucosidase inhibitors; bovine or porcineglucagon; somatostatins such as SANDOSTATIN™ (octreotide); anddiazoxides such as PROGLYCEM™ (diazoxide).

In an additional embodiment, the Therapeutics of the invention areadministered in combination with drugs effective in treating irondeficiency and hypochromic anemias, including but not limited to,ferrous sulfate (iron sulfate, FEOSOL™), ferrous fumarate (e.g.,FEOSTAT™), ferrous gluconate (e.g., FERGON™), polysaccharide-ironcomplex (e.g., NIFEREX™), iron dextran injection (e.g., INFED™), cupricsulfate, pyroxidine, riboflavin, Vitamin B₁₂, cyancobalamin injection(e.g., REDISOL™, RUBRAMIN PC™), hydroxocobalamin, folic acid (e.g.,FOLVITE™), leucovorin (folinic acid, 5-CHOH4PteGlu, citrovorum factor)or WELLCOVORIN (Calcium salt of leucovorin), transferrin or ferritin.

In another embodiment, Therapeutics of the invention are administered incombination with vasodilating agents and/or calcium channel blockingagents. Vasodilating agents that may be administered with theTherapeutics of the invention include, but are not limited to,Angiotensin Converting Enzyme (ACE) inhibitors (e.g., papaverine,isoxsuprine, benazepril, captopril, cilazapril, enalapril, enalaprilat,fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril,spirapril, trandolapril, and nylidrin), and nitrates (e.g., isosorbidedinitrate, isosorbide mononitrate, and nitroglycerin). Examples ofcalcium channel blocking agents that may be administered in combinationwith the Therapeutics of the invention include, but are not limited toamlodipine, bepridil, diltiazem, felodipine, flunarizine, isradipine,nicardipine, nifedipine, nimodipine, and verapamil.

In additional embodiments, the Therapeutics of the invention areadministered in combination with other therapeutic or prophylacticregimens, such as, for example, radiation therapy.

Example 14 Method of Treating Decreased Levels of the Polypeptide

The present invention relates to a method for treating an individual inneed of an increased level of a polypeptide of the invention in the bodycomprising administering to such an individual a composition comprisinga therapeutically effective amount of polypeptides (including agoniststhereto), and/or antibodies of the invention. Moreover, it will beappreciated that conditions caused by a decrease in the standard ornormal expression level of a polypeptide of the present invention in anindividual may be treated by administering agonists of said polypeptide.Thus, the invention also provides a method of treatment of an individualin need of an increased level of the polypeptide comprisingadministering to such an individual a Therapeutic comprising an amountof the agonist (including polypeptides and antibodies of the presentinvention) to increase the activity level of the polypeptide in such anindividual.

For example, a patient with decreased levels of a polypeptide receives adaily dose 0.1-100 ug/kg of the agonist for six consecutive days. Theexact details of the dosing scheme, based on administration andformulation, are provided in Example 13.

Example 15 Method of Treating Increased Levels of the Polypeptide

The present invention also relates to a method of treating an individualin need of a decreased level of a polypeptide of the invention in thebody comprising administering to such an individual a compositioncomprising a therapeutically effective amount of an antagonist of theinvention (including polypeptides and antibodies of the invention).

In one example, antisense technology is used to inhibit production of apolypeptide of the present invention. This technology is one example ofa method of decreasing levels of a polypeptide, due to a variety ofetiologies, such as cancer.

For example, a patient diagnosed with abnormally increased levels of apolypeptide is administered intravenously antisense polynucleotides at0.5, 1.0, 1.5, 2.0 and 3.0 mg/kg day for 21 days. This treatment isrepeated after a 7-day rest period if the treatment was well tolerated.The antisense polynucleotides of the present invention can be formulatedusing techniques and formulations described herein (e.g. see Example13), or otherwise known in the art.

Example 16 Method of Treatment Using Gene Therapy—Ex Vivo

One method of gene therapy transplants fibroblasts, which are capable ofexpressing a polypeptide, onto a patient. Generally, fibroblasts areobtained from a subject by skin biopsy. The resulting tissue is placedin tissue-culture medium and separated into small pieces. Small chunksof the tissue are placed on a wet surface of a tissue culture flask,approximately ten pieces are placed in each flask. The flask is turnedupside down, closed tight and left at room temperature over night. After24 hours at room temperature, the flask is inverted and the chunks oftissue remain fixed to the bottom of the flask and fresh media (e.g.,Ham's F12 media, with 10% FBS, penicillin and streptomycin) is added.The flasks are then incubated at 37 degree C. for approximately oneweek.

At this time, fresh media is added and subsequently changed everyseveral days. After an additional two weeks in culture, a monolayer offibroblasts emerge. The monolayer is trypsinized and scaled into largerflasks.

pMV-7 (Kirschmeier, P. T. et al., DNA, 7:219-25 (1988)), flanked by thelong terminal repeats of the Moloney murine sarcoma virus, is digestedwith EcoRI and HindIII and subsequently treated with calf intestinalphosphatase. The linear vector is fractionated on agarose gel andpurified, using glass beads.

The cDNA encoding a polypeptide of the present invention can beamplified using PCR primers which correspond to the 5′ and 3′ endsequences respectively as set forth in Example 1 using primers andhaving appropriate restriction sites and initiation/stop codons, ifnecessary. Preferably, the 5′ primer contains an EcORI site and the 3′primer includes a HindIII site. Equal quantities of the Moloney murinesarcoma virus linear backbone and the amplified EcORI and HindIIIfragment are added together, in the presence of T4 DNA ligase. Theresulting mixture is maintained under conditions appropriate forligation of the two fragments. The ligation mixture is then used totransform bacteria HBB101, which are then plated onto agar containingkanamycin for the purpose of confirming that the vector has the gene ofinterest properly inserted.

The amphotropic pA317 or GP+am12 packaging cells are grown in tissueculture to confluent density in Dulbecco's Modified Eagles Medium (DMEM)with 10% calf serum (CS), penicillin and streptomycin. The MSV vectorcontaining the gene is then added to the media and the packaging cellstransduced with the vector. The packaging cells now produce infectiousviral particles containing the gene (the packaging cells are nowreferred to as producer cells).

Fresh media is added to the transduced producer cells, and subsequently,the media is harvested from a 10 cm plate of confluent producer cells.The spent media, containing the infectious viral particles, is filteredthrough a millipore filter to remove detached producer cells and thismedia is then used to infect fibroblast cells. Media is removed from asub-confluent plate of fibroblasts and quickly replaced with the mediafrom the producer cells. This media is removed and replaced with freshmedia. If the titer of virus is high, then virtually all fibroblastswill be infected and no selection is required. If the titer is very low,then it is necessary to use a retroviral vector that has a selectablemarker, such as neo or his. Once the fibroblasts have been efficientlyinfected, the fibroblasts are analyzed to determine whether protein isproduced.

The engineered fibroblasts are then transplanted onto the host, eitheralone or after having been grown to confluence on cytodex 3 microcarrierbeads.

Example 17 Gene Therapy Using Endogenous Genes Corresponding ToPolynucleotides of the Invention

Another method of gene therapy according to the present inventioninvolves operably associating the endogenous polynucleotide sequence ofthe invention with a promoter via homologous recombination as described,for example, in U.S. Pat. No. 5,641,670, issued June InternationalPublication NO: WO 94/12650, published Aug. 4, 1994; Koller et al.,Proc. Natl. Acad. Sci. USA, 86:8932-8935 (1989); and Zijlstra et al.,Nature, 342:435438 (1989). This method involves the activation of a genewhich is present in the target cells, but which is not expressed in thecells, or is expressed at a lower level than desired.

Polynucleotide constructs are made which contain a promoter andtargeting sequences, which are homologous to the 5′ non-coding sequenceof endogenous polynucleotide sequence, flanking the promoter. Thetargeting sequence will be sufficiently near the 5′ end of thepolynucleotide sequence so the promoter will be operably linked to theendogenous sequence upon homologous recombination. The promoter and thetargeting sequences can be amplified using PCR. Preferably, theamplified promoter contains distinct restriction enzyme sites on the 5′and 3′ ends. Preferably, the 3′ end of the first targeting sequencecontains the same restriction enzyme site as the 5′ end of the amplifiedpromoter and the 5′ end of the second targeting sequence contains thesame restriction site as the 3′ end of the amplified promoter.

The amplified promoter and the amplified targeting sequences aredigested with the appropriate restriction enzymes and subsequentlytreated with calf intestinal phosphatase. The digested promoter anddigested targeting sequences are added together in the presence of T4DNA ligase. The resulting mixture is maintained under conditionsappropriate for ligation of the two fragments. The construct is sizefractionated on an agarose gel, then purified by phenol extraction andethanol precipitation.

In this Example, the polynucleotide constructs are administered as nakedpolynucleotides via electroporation. However, the polynucleotideconstructs may also be administered with transfection-facilitatingagents, such as liposomes, viral sequences, viral particles,precipitating agents, etc. Such methods of delivery are known in theart.

Once the cells are transfected, homologous recombination will take placewhich results in the promoter being operably linked to the endogenouspolynucleotide sequence. This results in the expression ofpolynucleotide corresponding to the polynucleotide in the cell.Expression may be detected by immunological staining, or any othermethod known in the art.

Fibroblasts are obtained from a subject by skin biopsy. The resultingtissue is placed in DMEM+10% fetal calf serum. Exponentially growing orearly stationary phase fibroblasts are trypsinized and rinsed from theplastic surface with nutrient medium. An aliquot of the cell suspensionis removed for counting, and the remaining cells are subjected tocentrifugation. The supernatant is aspirated and the pellet isresuspended in 5 ml of electroporation buffer (20 mM HEPES pH 7.3, 137mM NaCl, 5 mM KCl, 0.7 mM Na₂ HPO₄, 6 mM dextrose). The cells arerecentrifuged, the supernatant aspirated, and the cells resuspended inelectroporation buffer containing 1 mg/ml acetylated bovine serumalbumin. The final cell suspension contains approximately 3×10⁶cells/ml. Electroporation should be performed immediately followingresuspension.

Plasmid DNA is prepared according to standard techniques. For example,to construct a plasmid for targeting to the locus corresponding to thepolynucleotide of the invention, plasmid pUC18 (MBI Fermentas, Amherst,N.Y.) is digested with HindIII. The CMV promoter is amplified by PCRwith an XbaI site on the 5′ end and a BamHI site on the 3′ end. Twonon-coding sequences are amplified via PCR: one non-coding sequence(fragment 1) is amplified with a HindIII site at the 5′ end and an Xbasite at the 3′end; the other non-coding sequence (fragment 2) isamplified with a BamHI site at the 5′end and a HindIII site at the3′end. The CMV promoter and the fragments (1 and 2) are digested withthe appropriate enzymes (CMV promoter-XbaI and BamHI; fragment 1-XbaI;fragment 2-BamHI) and ligated together. The resulting ligation productis digested with HindIII, and ligated with the HindIII-digested pUC18plasmid.

Plasmid DNA is added to a sterile cuvette with a 0.4 cm electrode gap(Bio-Rad). The final DNA concentration is generally at least 120 μg/ml.0.5 ml of the cell suspension (containing approximately 1.5.×10⁶ cells)is then added to the cuvette, and the cell suspension and DNA solutionsare gently mixed. Electroporation is performed with a Gene-Pulserapparatus (Bio-Rad). Capacitance and voltage are set at 960 AF and250-300 V, respectively. As voltage increases, cell survival decreases,but the percentage of surviving cells that stably incorporate theintroduced DNA into their genome increases dramatically. Given theseparameters, a pulse time of approximately 14-20 mSec should be observed.

Electroporated cells are maintained at room temperature forapproximately 5 min, and the contents of the cuvette are then gentlyremoved with a sterile transfer pipette. The cells are added directly to10 ml of prewarmed nutrient media (DMEM with 15% calf serum) in a 10 cmdish and incubated at 37 degree C. The following day, the media isaspirated and replaced with 10 ml of fresh media and incubated for afurther 16-24 hours.

The engineered fibroblasts are then injected into the host, either aloneor after having been grown to confluence on cytodex 3 microcarrierbeads. The fibroblasts now produce the protein product. The fibroblastscan then be introduced into a patient as described above.

Example 18 Method of Treatment Using Gene Therapy—In Vivo

Another aspect of the present invention is using in vivo gene therapymethods to prevent, treat, and/or ameliorate cardiovascular diseases anddisorders. The gene therapy method relates to the introduction of nakednucleic acid (DNA, RNA, and antisense DNA or RNA) sequences into ananimal to increase or decrease the expression of the polypeptide. Thepolynucleotide of the present invention may be operatively linked to(i.e., associated with) a promoter or any other genetic elementsnecessary for the expression of the polypeptide by the target tissue.Such gene therapy and delivery techniques and methods are known in theart, see, for example, WO90/11092, WO98/11779; U.S. Pat. Nos. 5,693,622,5705151, 5580859; Tabata et al., Cardiovasc. Res. 35(3):470479 (1997);Chao et al., Pharmacol. Res. 35(6):517-522 (1997); Wolff, Neuromuscul.Disord. 7(5):314-318 (1997); Schwartz et al., Gene Ther. 3(5):405-411(1996); Tsurumi et al., Circulation 94(12):3281-3290 (1996)(incorporated herein by reference).

The polynucleotide constructs may be delivered by any method thatdelivers injectable materials to the cells of an animal, such as,injection into the interstitial space of tissues (heart, muscle, skin,lung, liver, intestine and the like). The polynucleotide constructs canbe delivered in a pharmaceutically acceptable liquid or aqueous carrier.

The term “naked” polynucleotide, DNA or RNA, refers to sequences thatare free from any delivery vehicle that acts to assist, promote, orfacilitate entry into the cell, including viral sequences, viralparticles, liposome formulations, lipofectin or precipitating agents andthe like. However, the polynucleotides of the present invention may alsobe delivered in liposome formulations (such as those taught in FelgnerP. L. et al. (1995) Ann. NY Acad. Sci. 772:126-139 and Abdallah B. etal. (1995) Biol. Cell 85(1):1-7) which can be prepared by methods wellknown to those skilled in the art.

The polynucleotide vector constructs used in the gene therapy method arepreferably constructs that will not integrate into the host genome norwill they contain sequences that allow for replication. Any strongpromoter known to those skilled in the art can be used for driving theexpression of DNA. Unlike other gene therapy techniques, one majoradvantage of introducing naked nucleic acid sequences into target cellsis the transitory nature of the polynucleotide synthesis in the cells.Studies have shown that non-replicating DNA sequences can be introducedinto cells to provide production of the desired polypeptide for periodsof up to six months.

The polynucleotide construct can be delivered to the interstitial spaceof tissues within an animal, including muscle, skin, brain, lung, liver,spleen, bone marrow, thymus, heart, lymph, blood, bone, cartilage,pancreas, kidney, gall bladder, stomach, intestine, testis, ovary,uterus, rectum, nervous system, eye, gland, and connective tissue.Interstitial space of the tissues comprises the intercellular fluid,mucopolysaccharide matrix among the reticular fibers of organ tissues,elastic fibers in the walls of vessels or chambers, collagen fibers offibrous tissues, or that same matrix within connective tissueensheathing muscle cells or in the lacunae of bone. It is similarly thespace occupied by the plasma of the circulation and the lymph fluid ofthe lymphatic channels. Delivery to the interstitial space of muscletissue is preferred for the reasons discussed below. They may beconveniently delivered by injection into the tissues comprising thesecells. They are preferably delivered to and expressed in persistent,non-dividing cells which are differentiated, although delivery andexpression may be achieved in non-differentiated or less completelydifferentiated cells, such as, for example, stem cells of blood or skinfibroblasts. In vivo muscle cells are particularly competent in theirability to take up and express polynucleotides.

For the naked polynucleotide injection, an effective dosage amount ofDNA or RNA will be in the range of from about 0.05 g/kg body weight toabout 50 mg/kg body weight. Preferably the dosage will be from about0.005 mg/kg to about 20 mg/kg and more preferably from about 0.05 mg/kgto about 5 mg/kg. Of course, as the artisan of ordinary skill willappreciate, this dosage will vary according to the tissue site ofinjection. The appropriate and effective dosage of nucleic acid sequencecan readily be determined by those of ordinary skill in the art and maydepend on the condition being treated and the route of administration.The preferred route of administration is by the parenteral route ofinjection into the interstitial space of tissues. However, otherparenteral routes may also be used, such as, inhalation of an aerosolformulation particularly for delivery to lungs or bronchial tissues,throat or mucous membranes of the nose. In addition, nakedpolynucleotide constructs can be delivered to arteries duringangioplasty by the catheter used in the procedure.

The dose response effects of injected polynucleotide in muscle in vivois determined as follows. Suitable template DNA for production of mRNAcoding for polypeptide of the present invention is prepared inaccordance with a standard recombinant DNA methodology. The templateDNA, which may be either circular or linear, is either used as naked DNAor complexed with liposomes. The quadriceps muscles of mice are theninjected with various amounts of the template DNA.

Five to six week old female and male Balb/C mice are anesthetized byintraperitoneal injection with 0.3 ml of 2.5% Avertin. A 1.5 cm incisionis made on the anterior thigh, and the quadriceps muscle is directlyvisualized. The template DNA is injected in 0.1 ml of carrier in a 1 ccsyringe through a 27 gauge needle over one minute, approximately 0.5 cmfrom the distal insertion site of the muscle into the knee and about 0.2cm deep. A suture is placed over the injection site for futurelocalization, and the skin is closed with stainless steel clips.

After an appropriate incubation time (e.g., 7 days) muscle extracts areprepared by excising the entire quadriceps. Every fifth 15 umcross-section of the individual quadriceps muscles is histochemicallystained for protein expression. A time course for protein expression maybe done in a similar fashion except that quadriceps from different miceare harvested at different times. Persistence of DNA in muscle followinginjection may be determined by Southern blot analysis after preparingtotal cellular DNA and HIRT supernatants from injected and control mice.The results of the above experimentation in mice can be used toextrapolate proper dosages and other treatment parameters in humans andother animals using naked DNA.

Example 19 Transgenic Animals

The polypeptides of the invention can also be expressed in transgenicanimals. Animals of any species, including, but not limited to, mice,rats, rabbits, hamsters, guinea pigs, pigs, micro-pigs, goats, sheep,cows and non-human primates, e.g., baboons, monkeys, and chimpanzees maybe used to generate transgenic animals. In a specific embodiment,techniques described herein or otherwise known in the art, are used toexpress polypeptides of the invention in humans, as part of a genetherapy protocol.

Any technique known in the art may be used to introduce the transgene(i.e., polynucleotides of the invention) into animals to produce thefounder lines of transgenic animals. Such techniques include, but arenot limited to, pronuclear microinjection (Paterson et al., Appl.Microbiol. Biotechnol. 40:691-698 (1994); Carver et al., Biotechnology(NY) 11:1263-1270 (1993); Wright et al., Biotechnology (NY) 9:830-834(1991); and Hoppe et al., U.S. Pat. No. 4,873,191 (1989)); retrovirusmediated gene transfer into germ lines (Van der Putten et al., Proc.Natl. Acad. Sci., USA 82:6148-6152 (1985)), blastocysts or embryos; genetargeting in embryonic stem cells (Thompson et al., Cell 56:313-321(1989)); electroporation of cells or embryos (Lo, 1983, Mol Cell. Biol.3:1803-1814 (1983)); introduction of the polynucleotides of theinvention using a gene gun (see, e.g., Ulmer et al., Science 259:1745(1993); introducing nucleic acid constructs into embryonic pleuripotentstem cells and transferring the stem cells back into the blastocyst; andsperm-mediated gene transfer (Lavitrano et al., Cell 57:717-723 (1989);etc. For a review of such techniques, see Gordon, “Transgenic Animals,”Intl. Rev. Cytol. 115:171-229 (1989), which is incorporated by referenceherein in its entirety.

Any technique known in the art may be used to produce transgenic clonescontaining polynucleotides of the invention, for example, nucleartransfer into enucleated oocytes of nuclei from cultured embryonic,fetal, or adult cells induced to quiescence (Campell et al., Nature380:64-66 (1996); Wilmut et al., Nature 385:810-813 (1997)).

The present invention provides for transgenic animals that carry thetransgene in all their cells, as well as animals which carry thetransgene in some, but not all their cells, i.e., mosaic animals orchimeric. The transgene may be integrated as a single transgene or asmultiple copies such as in concatamers, e.g., head-to-head tandems orhead-to-tail tandems. The transgene may also be selectively introducedinto and activated in a particular cell type by following, for example,the teaching of Lasko et al. (Lasko et al., Proc. Natl. Acad. Sci. USA89:62326236 (1992)). The regulatory sequences required for such acell-type specific activation will depend upon the particular cell typeof interest, and will be apparent to those of skill in the art. When itis desired that the polynucleotide transgene be integrated into thechromosomal site of the endogenous gene, gene targeting is preferred.Briefly, when such a technique is to be utilized, vectors containingsome nucleotide sequences homologous to the endogenous gene are designedfor the purpose of integrating, via homologous recombination withchromosomal sequences, into and disrupting the function of thenucleotide sequence of the endogenous gene. The transgene may also beselectively introduced into a particular cell type, thus inactivatingthe endogenous gene in only that cell type, by following, for example,the teaching of Gu et al. (Gu et al., Science 265:103-106 (1994)). Theregulatory sequences required for such a cell-type specific inactivationwill depend upon the particular cell type of interest, and will beapparent to those of skill in the art.

Once transgenic animals have been generated, the expression of therecombinant gene may be assayed utilizing standard techniques. Initialscreening may be accomplished by Southern blot analysis or PCRtechniques to analyze animal tissues to verify that integration of thetransgene has taken place. The level of mRNA expression of the transgenein the tissues of the transgenic animals may also be assessed usingtechniques which include, but are not limited to, Northern blot analysisof tissue samples obtained from the animal, in situ hybridizationanalysis, and reverse transcriptase-PCR (rt-PCR). Samples of transgenicgene-expressing tissue may also be evaluated immunocytochemically orimmunohistochemically using antibodies specific for the transgeneproduct.

Once the founder animals are produced, they may be bred, inbred,outbred, or crossbred to produce colonies of the particular animal.Examples of such breeding strategies include, but are not limited to:outbreeding of founder animals with more than one integration site inorder to establish separate lines; inbreeding of separate lines in orderto produce compound transgenics that express the transgene at higherlevels because of the effects of additive expression of each transgene;crossing of heterozygous transgenic animals to produce animalshomozygous for a given integration site in order to both augmentexpression and eliminate the need for screening of animals by DNAanalysis; crossing of separate homozygous lines to produce compoundheterozygous or homozygous lines; and breeding to place the transgene ona distinct background that is appropriate for an experimental model ofinterest.

Transgenic animals of the invention have uses which include, but are notlimited to, animal model systems useful in elaborating the biologicalfunction of polypeptides of the present invention, studying conditionsand/or disorders associated with aberrant expression, and in screeningfor compounds effective in ameliorating such conditions and/ordisorders.

Example 20 Knock-Out Animals

Endogenous gene expression can also be reduced by inactivating or“knocking out” the gene and/or its promoter using targeted homologousrecombination. (e.g., see Smithies et al., Nature 317:230-234 (1985);Thomas & Capecchi, Cell 51:503-512 (1987); Thompson et al., Cell5:313-321 (1989); each of which is incorporated by reference herein inits entirety). For example, a mutant, non-functional polynucleotide ofthe invention (or a completely unrelated DNA sequence) flanked by DNAhomologous to the endogenous polynucleotide sequence (either the codingregions or regulatory regions of the gene) can be used, with or withouta selectable marker and/or a negative selectable marker, to transfectcells that express polypeptides of the invention in vivo. In anotherembodiment, techniques known in the art are used to generate knockoutsin cells that contain, but do not express the gene of interest.Insertion of the DNA construct, via targeted homologous recombination,results in inactivation of the targeted gene. Such approaches areparticularly suited in research and agricultural fields wheremodifications to embryonic stem cells can be used to generate animaloffspring with an inactive targeted gene (e.g., see Thomas & Capecchi1987 and Thompson 1989, supra). However this approach can be routinelyadapted for use in humans provided the recombinant DNA constructs aredirectly administered or targeted to the required site in vivo usingappropriate viral vectors that will be apparent to those of skill in theart.

In further embodiments of the invention, cells that are geneticallyengineered to express the polypeptides of the invention, oralternatively, that are genetically engineered not to express thepolypeptides of the invention (e.g., knockouts) are administered to apatient in vivo. Such cells may be obtained from the patient (i.e.,animal, including human) or an MHC compatible donor and can include, butare not limited to fibroblasts, bone marrow cells, blood cells (e.g.,lymphocytes), adipocytes, muscle cells, endothelial cells etc. The cellsare genetically engineered in vitro using recombinant DNA techniques tointroduce the coding sequence of polypeptides of the invention into thecells, or alternatively, to disrupt the coding sequence and/orendogenous regulatory sequence associated with the polypeptides of theinvention, e.g., by transduction (using viral vectors, and preferablyvectors that integrate the transgene into the cell genome) ortransfection procedures, including, but not limited to, the use ofplasmids, cosmids, YACs, naked DNA, electroporation, liposomes, etc. Thecoding sequence of the polypeptides of the invention can be placed underthe control of a strong constitutive or inducible promoter orpromoter/enhancer to achieve expression, and preferably secretion, ofthe polypeptides of the invention. The engineered cells which expressand preferably secrete the polypeptides of the invention can beintroduced into the patient systemically, e.g., in the circulation, orintraperitoneally.

Alternatively, the cells can be incorporated into a matrix and implantedin the body, e.g., genetically engineered fibroblasts can be implantedas part of a skin graft; genetically engineered endothelial cells can beimplanted as part of a lymphatic or vascular graft. (See, for example,Anderson et al. U.S. Pat. No. 5,399,349; and Mulligan & Wilson, U.S.Pat. No. 5,460,959 each of which is incorporated by reference herein inits entirety).

When the cells to be administered are non-autologous or non-MHCcompatible cells, they can be administered using well known techniqueswhich prevent the development of a host immune response against theintroduced cells. For example, the cells may be introduced in anencapsulated form which, while allowing for an exchange of componentswith the immediate extracellular environment, does not allow theintroduced cells to be recognized by the host immune system.

Transgenic and “knock-out” animals of the invention have uses whichinclude, but are not limited to, animal model systems useful inelaborating the biological function of polypeptides of the presentinvention, studying conditions and/or disorders associated with aberrantexpression, and in screening for compounds effective in amelioratingsuch conditions and/or disorders.

Example 21 Biological Effects of Agonists or Antagonists of theInvention

Fibroblast and Endothelial Cell Assays

Human lung fibroblasts are obtained from Clonetics (San Diego, Calif.)and maintained in growth media from Clonetics. Dermal microvascularendothelial cells are obtained from Cell Applications (San Diego,Calif.). For proliferation assays, the human lung fibroblasts and dermalmicrovascular endothelial cells can be cultured at 5,000 cells/well in a96-well plate for one day in growth medium. The cells are then incubatedfor one day in 0.1% BSA basal medium. After replacing the medium withfresh 0.1% BSA medium, the cells are incubated with the test proteinsfor 3 days. Alamar Blue (Alamar Biosciences, Sacramento, Calif.) isadded to each well to a final concentration of 10%. The cells areincubated for 4 hr. Cell viability is measured by reading in a CytoFluorfluorescence reader. For the PGE2 assays, the human lung fibroblasts arecultured at 5,000 cells/well in a 96-well plate for one day. After amedium change to 0.1% BSA basal medium, the cells are incubated withFGF-2 or agonists or antagonists of the invention with or without EL-lafor 24 hours. The supernatants are collected and assayed for PGE by EIAkit (Cayman, Ann Arbor, Mich.). For the IL-6 assays, the human lungfibroblasts are cultured at 5,000 cells/well in a 96-well plate for oneday. After a medium change to 0.1% BSA basal medium, the cells areincubated with FGF-2 or with or without agonists or antagonists of theinvention IL-1a for 24 hours. The supernatants are collected and assayedfor IL-6 by ELISA kit (Endogen, Cambridge, Mass.).

Human lung fibroblasts are cultured with FGF-2 or agonists orantagonists of the invention for 3 days in basal medium before theaddition of Alamar Blue to assess effects on growth of the fibroblasts.FGF-2 should show a stimulation at 10-2500 ng/ml which can be used tocompare stimulation with agonists or antagonists of the invention.

Example 22 The Effect of Agonists or Antagonists of the Invention on theGrowth of Vascular Endothelial Cells

On day 1, human umbilical vein endothelial cells (HUVEC) are seeded at2-5×10⁴ cells/35 mm dish density in M199 medium containing 4% fetalbovine serum (FBS), 16 units/ml heparin, and 50 units/ml endothelialcell growth supplements (ECGS, Biotechnique, Inc.). On day 2, the mediumis replaced with M199 containing 10% FBS, 8 units/ml heparin. An agonistor antagonist of the invention, and positive controls, such as VEGF andbasic FGF (bFGF) are added, at varying concentrations. On days 4 and 6,the medium is replaced. On day 8, cell number is determined with aCoulter Counter.

An increase in the number of HUVEC cells indicates that the compound ofthe invention may proliferate vascular endothelial cells, while adecrease in the number of HUVEC cells indicates that the compound of theinvention inhibits vascular endothelial cells.

The studies described in this example tested activity of a polypeptideof the invention. However, one skilled in the art could easily modifythe exemplified studies to test the activity of polynucleotides (e.g.,gene therapy), agonists, and/or antagonists of the invention.

Example 23 Lymphadema Animal Model

The purpose of this experimental approach is to create an appropriateand consistent lymphedema model for testing the therapeutic effects ofan agonist or antagonist of the invention in lymphangiogenesis andre-establishment of the lymphatic circulatory system in the rat hindlimb. Effectiveness is measured by swelling volume of the affected limb,quantification of the amount of lymphatic vasculature, total bloodplasma protein, and histopathology. Acute lymphedema is observed for7-10 days. Perhaps more importantly, the chronic progress of the edemais followed for up to 34 weeks.

Prior to beginning surgery, blood sample is drawn for proteinconcentration analysis. Male rats weighing approximately ˜350 g aredosed with Pentobarbital. Subsequently, the right legs are shaved fromknee to hip. The shaved area is swabbed with gauze soaked in 70% EtOH.Blood is drawn for serum total protein testing. Circumference andvolumetric measurements are made prior to injecting dye into paws aftermarking 2 measurement levels (0.5 cm above heel, at mid-pt of dorsalpaw). The intradermal dorsum of both right and left paws are injectedwith 0.05 ml of 1% Evan's Blue. Circumference and volumetricmeasurements are then made following injection of dye into paws.

Using the knee joint as a landmark, a mid-leg inguinal incision is madecircumferentially allowing the femoral vessels to be located. Forcepsand hemostats are used to dissect and separate the skin flaps. Afterlocating the femoral vessels, the lymphatic vessel that runs along sideand underneath the vessel(s) is located. The main lymphatic vessels inthis area are then electrically coagulated or suture ligated.

Using a microscope, muscles in back of the leg (near the semitendinosisand adductors) are bluntly dissected. The popliteal lymph node is thenlocated. The 2 proximal and 2 distal lymphatic vessels and distal bloodsupply of the popliteal node are then ligated by suturing. The popliteallymph node, and any accompanying adipose tissue, is then removed bycutting connective tissues.

Care is taken to control any mild bleeding resulting from thisprocedure. After lymphatics are occluded, the skin flaps are sealed byusing liquid skin (Vetbond) (AJ Buck). The separated skin edges aresealed to the underlying muscle tissue while leaving a gap of ˜0.5 cmaround the leg. Skin also may be anchored by suturing to underlyingmuscle when necessary.

To avoid infection, animals are housed individually with mesh (nobedding). Recovering animals are checked daily through the optimaledematous peak, which typically occurred by day 5-7. The plateauedematous peak are then observed. To evaluate the intensity of thelymphedema, the circumference and volumes of 2 designated places on eachpaw before operation and daily for 7 days are measured. The effect ofplasma proteins on lymphedema is determined and whether protein analysisis a useful testing perimeter is also investigated. The weights of bothcontrol and edematous limbs are evaluated at 2 places. Analysis isperformed in a blind manner.

Circumference Measurements: Under brief gas anesthetic to prevent limbmovement, a cloth tape is used to measure limb circumference.Measurements are done at the ankle bone and dorsal paw by 2 differentpeople and those 2 readings are averaged. Readings are taken from bothcontrol and edematous limbs.

Volumetric Measurements: On the day of surgery, animals are anesthetizedwith Pentobarbital and are tested prior to surgery. For dailyvolumetrics animals are under brief halothane anesthetic (rapidimmobilization and quick recovery), and both legs are shaved and equallymarked using waterproof marker on legs. Legs are first dipped in water,then dipped into instrument to each marked level then measured by Buxcoedema software (Chen/Victor). Data is recorded by one person, while theother is dipping the limb to marked area.

Blood-plasma protein measurements: Blood is drawn, spun, and serumseparated prior to surgery and then at conclusion for total protein andCa2⁺ comparison.

Limb Weight Comparison: After drawing blood, the animal is prepared fortissue collection. The limbs are amputated using a quillitine, then bothexperimental and control legs are cut at the ligature and weighed. Asecond weighing is done as the tibio-cacaneal joint is disarticulatedand the foot is weighed.

Histological Preparations: The transverse muscle located behind the knee(popliteal) area is dissected and arranged in a metal mold, filled withfreezeGel, dipped into cold methylbutane, placed into labeled samplebags at −80 EC until sectioning. Upon sectioning, the muscle is observedunder fluorescent microscopy for lymphatics.

The studies described in this example tested activity of agonists orantagonists of the invention. However, one skilled in the art couldeasily modify the exemplified studies to test the activity ofpolynucleotides or polypeptides of the invention (e.g., gene therapy).

Example 24 Suppression of TNF Alpha-Induced Adhesion Molecule Expressionby an Agonist or Antagonist of the Invention

The recruitment of lymphocytes to areas of inflammation and angiogenesisinvolves specific receptor-ligand interactions between cell surfaceadhesion molecules (CAMs) on lymphocytes and the vascular endotheliumThe adhesion process, in both normal and pathological settings, followsa multi-step cascade that involves intercellular adhesion molecule-1(ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and endothelialleukocyte adhesion molecule-1 (E-selectin) expression on endothelialcells (EC). The expression of these molecules and others on the vascularendothelium determines the efficiency with which leukocytes may adhereto the local vasculature and extravasate into the local tissue duringthe development of an inflammatory response. The local concentration ofcytokines and growth factor participate in the modulation of theexpression of these CAMs.

Tumor necrosis factor alpha (TNF-a), a potent proinflammatory cytokine,is a stimulator of all three CAMs on endothelial cells and may beinvolved in a wide variety of inflammatory responses, often resulting ina pathological outcome.

The potential of an agonist or antagonist of the invention to mediate asuppression of TNF-a induced CAM expression can be examined. A modifiedELISA assay which uses ECs as a solid phase absorbent is employed tomeasure the amount of CAM expression on TNF-a treated ECs whenco-stimulated with a member of the FGF family of proteins.

To perform the experiment, human umbilical vein endothelial cell (HUVEC)cultures are obtained from pooled cord harvests and maintained in growthmedium (EGM-2; Clonetics, San Diego, Calif.) supplemented with 10% FCSand 1% penicillin/streptomycin in a 37 degree C. humidified incubatorcontaining 5% CO₂. HUVECs are seeded in 96-well plates at concentrationsof 1×10⁴ cells/well in EGM medium at 37 degree C. for 18-24 hrs or untilconfluent. The monolayers are subsequently washed 3 times with aserum-free solution of RPMI-1640 supplemented with 100 U/ml penicillinand 100 mg/ml streptomycin, and treated with a given cytokine and/orgrowth factor(s) for 24 h at 37 degree C. Following incubation, thecells are then evaluated for CAM expression.

Human Umbilical Vein Endothelial cells (HUVECs) are grown in a standard96 well plate to confluence. Growth medium is removed from the cells andreplaced with 90 ul of 199 Medium (10% FBS). Samples for testing andpositive or negative controls are added to the plate in triplicate (in10 ul volumes). Plates are incubated at 37 degree C. for either 5 h(selectin and integrin expression) or 24 h (integrin expression only).Plates are aspirated to remove medium and 100 μl of 0.1%paraformaldehyde-PBS(with Ca++ and Mg++) is added to each well. Platesare held at 4° C. for 30 min.

Fixative is then removed from the wells and wells are washed 1× withPBS(+Ca,Mg)+0.5% BSA and drained. Do not allow the wells to dry. Add 10μl of diluted primary antibody to the test and control wells.Anti-ICAM-1-Biotin, Anti-VCAM-1-Biotin and Anti-E-selectin-Biotin areused at a concentration of 10 μg/ml (1:10 dilution of 0.1 mg/ml stockantibody). Cells are incubated at 37° C. for 30 min. in a humidifiedenvironment. Wells are washed X3 with PBS(+Ca,Mg)+0.5% BSA.

Then add 20 μl of diluted ExtrAvidin-Alkaline Phosphotase (1:5,000dilution) to each well and incubated at 37° C. for 30 min. Wells arewashed X3 with PBS(+Ca,Mg)+0.5% BSA. 1 tablet of p-Nitrophenol PhosphatepNPP is dissolved in 5 ml of glycine buffer (pH 10.4). 100 μl of pNPPsubstrate in glycine buffer is added to each test well. Standard wellsin triplicate are prepared from the working dilution of theExtrAvidin-Alkaline Phosphotase in glycine buffer: 1:5,000(10⁰)>10^(−0.5)>10⁻¹>10^(−1.5). 5 μl of each dilution is added totriplicate wells and the resulting AP content in each well is 5.50 ng,1.74 ng, 0.55 ng, 0.18 ng. 100 μl of pNNP reagent must then be added toeach of the standard wells. The plate must be incubated at 37° C. for 4h. A volume of 50 μl of 3M NaOH is added to all wells. The results arequantified on a plate reader at 405 nm The background subtraction optionis used on blank wells filled with glycine buffer only. The template isset up to indicate the concentration of AP-conjugate in each standardwell [5.50 ng; 1.74 ng; 0.55 ng; 0.18 ng]. Results are indicated asamount of bound AP-conjugate in each sample.

The studies described in this example tested activity of agonists orantagonists of the invention. However, one skilled in the art couldeasily modify the exemplified studies to test the activity ofpolynucleotides or polypeptides of the invention (e.g., gene therapy).

Example 25 Production Of Polypeptide of the Invention ForHigh-Throughput Screening Assays

The following protocol produces a supernatant containing polypeptide ofthe present invention to be tested. This supernatant can then be used inthe Screening Assays described in Examples 27-30.

First, dilute Poly-D-Lysine (644 587 Boehringer-Mannheim) stock solution(1 mg/ml in PBS) 1:20 in PBS (w/o calcium or magnesium 17-516FBiowhittaker) for a working solution of 50 ug/ml. Add 200 ul of thissolution to each well (24 well plates) and incubate at RT for 20minutes. Be sure to distribute the solution over each well (note: a12-channel pipetter may be used with tips on every other channel).Aspirate off the Poly-D-Lysine solution and rinse with 1 ml PBS(Phosphate Buffered Saline). The PBS should remain in the well untiljust prior to plating the cells and plates may be poly-lysine coated inadvance for up to two weeks.

Plate 293T cells (do not carry cells past P+20) at 2×10⁵ cells/well in0.5 ml DMEM(Dulbecco's Modified Eagle Medium)(with 4.5 G/L glucose andL-glutamine (12-604F Biowhittaker))/10% heat inactivated FBS(14-503FBiowhittaker)/1× Penstrep(17-602E Biowhittaker). Let the cells growovernight.

The next day, mix together in a sterile solution basin: 300 ulLipofectamine (18324-012 Gibco/BRL) and 5 ml Optimem I (31985070Gibco/BRL)/96-well plate. With a small volume multi-channel pipetter,aliquot approximately 2 ug of an expression vector containing apolynucleotide insert, produced by the methods described in Examples8-10, into an appropriately labeled 96-well round bottom plate. With amulti-channel pipetter, add 50 ul of the Lipofectamine/Optimem I mixtureto each well. Pipette up and down gently to mix. Incubate at RT 15-45minutes. After about 20 minutes, use a multi-channel pipetter to add 150ul Optimem I to each well. As a control, one plate of vector DNA lackingan insert should be transfected with each set of transfections.

Preferably, the transfection should be performed by tag-teaming thefollowing tasks. By tag-teaming, hands on time is cut in half, and thecells do not spend too much time on PBS. First, person A aspirates offthe media from four 24-well plates of cells, and then person B rinseseach well with 0.5-1 ml PBS. Person A then aspirates off PBS rinse, andperson B, using a 12-channel pipetter with tips on every other channel,adds the 200 ul of DNA/Lipofectamine/Optimem I complex to the odd wellsfirst, then to the even wells, to each row on the 24-well plates.Incubate at 37 degree C. for 6 hours.

While cells are incubating, prepare appropriate media, either 1% BSA inDMEM with 1× penstrep, or HGS CHO-5 media (116.6 mg/L of CaCl₂ (anhyd);0.00130 mg/L CuSO₄—5H₂O; 0.050 mg/L of Fe(NO₃)₃—9H₂O; 0.417 mg/L ofFeSO₄—7H₂O; 311.80 mg/L of Kcl; 28.64 mg/L of MgCl₂; 48.84 mg/L ofMgSO₄; 6995.50 mg/L of NaCl; 2400.0 mg/L of NaHCO₃; 62.50 mg/L ofNaH₂PO₄—H₂O; 71.02 mg/L of Na₂HPO4; 0.4320 mg/L of ZnSO₄—7H₂O; 0.002mg/L of Arachidonic Acid; 1.022 mg/L of Cholesterol; 0.070 mg/L ofDL-alpha-Tocopherol-Acetate; 0.0520 mg/L of Linoleic Acid; 0.010 mg/L ofLinolenic Acid; 0.010 mg/L of Myristic Acid; 0.010 mg/L of Oleic Acid;0.010 mg/L of Palmitric Acid; 0.010 mg/L of Palmitic Acid; 100 mg/L ofPluronic F-68; 0.010 mg/L of Stearic Acid; 2.20 mg/L of Tween 80; 4551mg/L of D-Glucose;

-   -   130.85 mg/ml of L-Alanine; 147.50 mg/ml of L-Arginine-HCL; 7.50        mg/ml of L-Asparagine-H₂O; 6.65 mg/ml of L-Aspartic Acid; 29.56        mg/ml of L-Cystine-2HCL-H₂O; 31.29 mg/ml of L-Cystine-2HCL; 7.35        mg/ml of L-Glutamic Acid; 365.0 mg/ml of L-Glutamine; 18.75        mg/ml of Glycine; 52.48 mg/ml of L-Histidine-HCL-H₂O; 106.97        mg/ml of L-Isoleucine; 111.45 mg/ml of L-Leucine; 163.75 mg/ml        of L-Lysine HCL; 32.34 mg/ml of L-Methionine; 68.48 mg/ml of        L-Phenylalainine; 40.0 mg/ml of L-Proline; 26.25 mg/ml of        L-Serine; 101.05 mg/ml of L-Threonine; 19.22 mg/ml of        L-Tryptophan; 91.79 mg/ml of L-Tryrosine-2Na-2H₂O; and 99.65        mg/ml of L-Valine; 0.0035 mg/L of Biotin; 3.24 mg/L of D-Ca        Pantothenate; 11.78 mg/L of Choline Chloride; 4.65 mg/L of Folic        Acid; 15.60 mg/L of i-Inositol; 3.02 mg/L of Niacinamide; 3.00        mg/L of Pyridoxal HCL; 0.031 mg/L of Pyridoxine HCL; 0.319 mg/L        of Riboflavin; 3.17 mg/L of Thiamine HCL; 0.365 mg/L of        Thymidine; 0.680 mg/L of Vitamin B₁₂; 25 mM of HEPES Buffer;        2.39 mg/L of Na Hypoxanthine; 0.105 mg/L of Lipoic Acid; 0.081        mg/L of Sodium Putrescine-2HCL; 55.0 mg/L of Sodium Pyruvate;        0.0067 mg/L of Sodium Selenite; 20 uM of Ethanolamine; 0.122        mg/L of Ferric Citrate; 41.70 mg/L of Methyl-B-Cyclodextrin        complexed with Linoleic Acid; 33.33 mg/L of        Methyl-B-Cyclodextrin complexed with Oleic Acid; 10 mg/L of        Methyl-B-Cyclodextrin complexed with Retinal Acetate. Adjust        osmolarity to 327 mOsm) with 2 mm glutamine and 1× penstrep.        (BSA (81-068-3 Bayer) 100 gm dissolved in 1 L DMEM for a 10% BSA        stock solution). Filter the media and collect 50 ul for        endotoxin assay in 15 ml polystyrene conical.

The transfection reaction is terminated, preferably by tag-teaming, atthe end of the incubation period. Person A aspirates off thetransfection media, while person B adds 1.5 ml appropriate media to eachwell. Incubate at 37 degree C. for 45 or 72 hours depending on the mediaused: 1% BSA for 45 hours or CHO-5 for 72 hours.

On day four, using a 300 ul multichannel pipetter, aliquot 600 ul in one1 ml deep well plate and the remaining supernatant into a 2 ml deepwell. The supernatants from each well can then be used in the assaysdescribed in Examples 27-30.

It is specifically understood that when activity is obtained in any ofthe assays described below using a supernatant, the activity originatesfrom either the polypeptide of the present invention directly (e.g., asa secreted protein) or by polypeptide of the present invention inducingexpression of other proteins, which are then secreted into thesupernatant. Thus, the invention further provides a method ofidentifying the protein in the supernatant characterized by an activityin a particular assay.

Example 26 Construction of GAS Reporter Construct

One signal transduction pathway involved in the differentiation andproliferation of cells is called the Jaks-STATs pathway. Activatedproteins in the Jaks-STATs pathway bind to gamma activation site “GAS”elements or interferon-sensitive responsive element (“ISRE”), located inthe promoter of many genes. The binding of a protein to these elementsalter the expression of the associated gene.

GAS and ISRE elements are recognized by a class of transcription factorscalled Signal Transducers and Activators of Transcription, or “STATs.”There are six members of the STATs family. Stat1 and Stat3 are presentin many cell types, as is Stat2 (as response to MN-alpha is widespread).Stat4 is more restricted and is not in many cell types though it hasbeen found in T helper class I, cells after treatment with IL-12. Stat5was originally called mammary growth factor, but has been found athigher concentrations in other cells including myeloid cells. It can beactivated in tissue culture cells by many cytokines.

The STATs are activated to translocate from the cytoplasm to the nucleusupon tyrosine phosphorylation by a set of kinases known as the JanusKinase (“Jaks”) family. Jaks represent a distinct family of solubletyrosine kinases and include Tyk2, Jak1, Jak2, and Jak3. These kinasesdisplay significant sequence similarity and are generally catalyticallyinactive in resting cells.

The Jaks are activated by a wide range of receptors summarized in theTable below. (Adapted from review by Schidler and Darnell, Ann. Rev.Biocheum 64:621-51 (1995)). A cytokine receptor family, capable ofactivating Jaks, is divided into two groups: (a) Class 1 includesreceptors for IL-2, IL-3, IL-4, IL-6, IL-7, IL-9, IL-li, IL-12, IL-15,Epo, PRL, GH, G-CSF, GM-CSF, LIF, CNTF, and thrombopoietin; and (b)Class 2 includes IFN-a, IPN-g, and IL-10. The Class 1 receptors share aconserved cysteine motif (a set of four conserved cysteines and onetryptophan) and a WSXWS motif (a membrane proximal region encodingTrp-Ser-Xaa-Trp-Ser (SEQ ID NO: 2)).

Thus, on binding of a ligand to a receptor, Jaks are activated, which inturn activate STATs, which then translocate and bind to GAS elements.This entire process is encompassed in the Jaks-STATs signal transductionpathway. Therefore, activation of the Jaks-STATs pathway, reflected bythe binding of the GAS or the ISRE element, can be used to indicateproteins involved in the proliferation and differentiation of cells. Forexample, growth factors and cytokines are known to activate theJaks-STATs pathway (See Table below). Thus, by using GAS elements linkedto reporter molecules, activators of the Jaks-STATs pathway can beidentified. JAKs Ligand tyk2 Jak1 Jak2 Jak3 STATS GAS (elements) or ISREIFN family IFN-a/B + + − − 1, 2, 3 ISRE IFN-g + + − 1 GAS (IRF1 > Lys6 >IFP) Il-10 + ? ? − 1, 3 gp130 family IL-6 (Pleiotropic) + + + ? 1, 3 GAS(IRF1 > Lys6 > IFP) Il-11 (Pleiotropic) ? + ? ? 1, 3 OnM (Pleiotropic)? + + ? 1, 3 LIF (Pleiotropic) ? + + ? 1, 3 CNTF (Pleiotropic) −/+ + + ?1, 3 G-CSF (Pleiotropic) ? + ? ? 1, 3 IL-12 (Pleiotropic) + − + + 1, 3g-C family IL-2 (lymphocytes) − + − + 1, 3, 5 GAS IL-4 (lymph/myeloid)− + − + 6 GAS (IRF1 = IFP >> Ly6)(IgH) IL-7 (lymphocytes) − + − + 5 GASIL-9 (lymphocytes) − + − + 5 GAS IL-13 (lymphocyte) − + ? ? 6 GAS IL-15? + ? + 5 GAS gp140 family IL-3 (myeloid) − − + − 5 GAS (IRF1 > IFP >>Ly6) IL-5 (myeloid) − − + − 5 GAS GM-CSF (myeloid) − − + − 5 GAS Growthhormone family GH ? − + − 5 PRL ? +/− + − 1, 3, 5 EPO ? − + − 5 GAS(B-CAS > IRF1 = IFP >> Ly6) Receptor Tyrosine Kinases EGF ? + + − 1, 3GAS (IRF1) PDGF ? + + − 1, 3 CSF-1 ? + + − 1, 3 GAS (not IRF1)

To construct a synthetic GAS containing promoter element, a PCR basedstrategy is employed to generate a GAS-SV40 promoter sequence. The 5′primer contains four tandem copies of the GAS binding site found in theIRF1 promoter and previously demonstrated to bind STATs upon inductionwith a range of cytokines (Rothman et al., Immunity 1:457468 (1994).),although other GAS or ISRE elements can be used instead. The 5′ primeralso contains 18 bp of sequence complementary to the SV40 early promotersequence and is flanked with an XhoI site. The sequence of the 5′ primeris: 5′:GCGCCTCGAGATTTCCCCGAAATCTAGATTTCCCCGAAATGATTTCCCCG (SEQ ID NO: 3)AAATGATTTCCCCGAAATATCTGCCATCTCAATTAG:3′

The downstream primer is complementary to the SV40 promoter and isflanked with a Hind m site: 5′:GCGGCAAGCTTTTTGCAAAGCCTAGGC:3′ (SEQ IDNO: 4)

PCR amplification is performed using the SV40 promoter template presentin the B-gal:promoter plasmid obtained from Clontech. The resulting PCRfragment is digested with XhoI/Hind III and subcloned into BLSK2-.(Stratagene.) Sequencing with forward and reverse primers confirms thatthe insert contains the following sequence:5′:CTCGAGATTTCCCCGAAATCTAGATTTCCCCGAAATGATTTCCCCGAAAT (SEQ ID NO: 5)GATTTCCCCGAAATATCTGCCATCTCAATTAGTCAGCAACCATAGTCCCGCCCCTAACTCCGCCCATCCCGCCCCTAACTCCGCCCAGTTCCGCCCATTCTCCGCCCCATGGCTGACTAATTTTTTTTATTTATGCAGAGGCCGAGGCCGCCTCGGCCTCTGAGCTATTCCAGAAGTAGTGAGGAGGCTTTTTTGGAGGCCTAGGCTTTTGCAAAAAGCTT:3′

With this GAS promoter element linked to the SV40 promoter, a GAS:SEAP2reporter construct is next engineered. Here, the reporter molecule is asecreted alkaline phosphatase, or “SEAP.” Clearly, however, any reportermolecule can be instead of SEAP, in this or in any of the otherExamples. Well known reporter molecules that can be used instead of SEAPinclude chloramphenicol acetyltransferase (CAT), luciferase, alkalinephosphatase, B-galactosidase, green fluorescent protein (GFP), or anyprotein detectable by an antibody.

The above sequence confirmed synthetic GAS-SV40 promoter element issubcloned into the pSEAP-Promoter vector obtained from Clontech usingHindIII and XhoI, effectively replacing the SV40 promoter with theamplified GAS:SV40 promoter element, to create the GAS-SEAP vector.However, this vector does not contain a neomycin resistance gene, andtherefore, is not preferred for mammalian expression systems.

Thus, in order to generate mammalian stable cell lines expressing theGAS-SEAP reporter, the GAS-SEAP cassette is removed from the GAS-SEAPvector using SalI and NotI, and inserted into a backbone vectorcontaining the neomycin resistance gene, such as pGFP-1 (Clontech),using these restriction sites in the multiple cloning site, to createthe GAS-SEAP/Neo vector. Once this vector is transfected into mammaliancells, this vector can then be used as a reporter molecule for GASbinding.

Other constructs can be made using the above description and replacingGAS with a different promoter sequence. However, many other promoterscan be substituted using the protocols described in these Examples. Forinstance, SRE, IL-2, NFAT, or Osteocalcin promoters can be substituted,alone or in combination (e.g., GAS/NF-KB/EGR, GAS/NF-KB, Il-2/NFAT, orNF-KB/GAS). Similarly, other cell lines can be used to test reporterconstruct activity, such as HELA (epithelial), HUVEC (endothelial), Reh(B-cell), Saos-2 (osteoblast), HUVAC (aortic), or

Example 27 Assay for SEAP Activity

As a reporter molecule for the assays, SEAP activity is assayed usingthe Tropix Phospho-light Kit (Cat. BP-400) according to the followinggeneral procedure. The Tropix Phospho-light Kit supplies the Dilution,Assay, and Reaction Buffers used below.

Prime a dispenser with the 2.5× Dilution Buffer and dispense 15 ul of2.5× dilution buffer into Optiplates containing 35 ul of a supernatant.Seal the plates with a plastic sealer and incubate at 65 degree C for 30min. Separate the Optiplates to avoid uneven heating.

Cool the samples to room temperature for 15 minutes. Empty the dispenserand prime with the Assay Buffer. Add 50 ml Assay Buffer and incubate atroom temperature 5 min. Empty the dispenser and prime with the ReactionBuffer (see the Table below). Add 50 ul Reaction Buffer and incubate atroom temperature for 20 minutes. Since the intensity of thechemiluminescent signal is time dependent, and it takes about 10 minutesto read 5 plates on a luminometer, thus one should treat 5 plates ateach time and start the second set 10 minutes later.

Read the relative light unit in the luminometer. Set H12 as blank, andprint the results. An increase in chemiluminescence indicates reporteractivity. Reaction Buffer Formulation: Rxn buffer # of plates diluent(ml) CSPD (ml) 10 60 3 11 65 3.25 12 70 3.5 13 75 3.75 14 80 4 15 854.25 16 90 4.5 17 95 4.75 18 100 5 19 105 5.25 20 110 5.5 21 115 5.75 22120 6 23 125 6.25 24 130 6.5 25 135 6.75 26 140 7 27 145 7.25 28 150 7.529 155 7.75 30 160 8 31 165 8.25 32 170 8.5 33 175 8.75 34 180 9 35 1859.25 36 190 9.5 37 195 9.75 38 200 10 39 205 10.25 40 210 10.5 41 21510.75 42 220 11 43 225 11.25 44 230 11.5 45 235 11.75 46 240 12 47 24512.25 48 250 12.5 49 255 12.75 50 260 13

Example 28 High-Throughput Screening Assay Identifying Changes in SmallMolecule Concentration and Membrane Permeability

Binding of a ligand to a receptor is known to alter intracellular levelsof small molecules such as calcium, potassium, sodium, and pH, as wellas alter membrane potential. These alterations can be measured in anassay to identify supernatants which bind to receptors of a particularcell. Although the following protocol describes an assay for calcium,this protocol can easily be modified to detect changes in potassium,sodium, pH, membrane potential, or any other small molecule which isdetectable by a fluorescent probe.

The following assay uses Fluorometric Imaging Plate Reader (“FLIPR”) tomeasure changes in flourescent molecules Molecular Probes) that bindsmall molecules. Clearly, any flourescent molecule detecting a smallmolecule can be used instead of the calcium fluorescent molecule, fluo-4(Molecular Probes, Inc.; catalog no. F-14202), used here.

For adherent cells, seed the cells at 10,000-20,000 cells/well in aCo-star black 96-well plate with clear bottom. The plate is incubated ina CO₂ incubator for 20 hours. The adherent cells are washed two times inBiotek washer with 200 ul of HBSS (Hank's Balanced Salt Solution)leaving 100 ul of buffer after the final wash.

A stock solution of 1 mg/ml fluo-4 is made in 10% pluronic acid DMSO. Toload the cells with fluo-4, 50 ul of 12 ug/ml fluo-4 is added to eachwell. The plate is incubated at 37 degrees C. in a CO₂ incubator for 60min. The plate is washed four times in the Biotek washer with HBSSleaving 100 ul of buffer.

For non-adherent cells, the cells are spun down from culture media.Cells are re-suspended to 2-5×10⁶ cells/ml with HBSS in a 50-nil conicaltube. 4 ul of 1 mg/ml fluo-4 solution in 10% pluronic acid DMSO is addedto each ml of cell suspension. The tube is then placed in a 37 degreesC. water bath for 30-60 min. The cells are washed twice with HBSS,resuspended to 1×10⁶ cells/ml, and dispensed into a microplate, 100ul/well. The plate is centrifuged at 1000 rpm for 5 min. The plate isthen washed once in Denley Cell Wash with 200 ul, followed by anaspiration step to 100 ul final volume.

For a non-cell based assay, each well contains a fluorescent molecule,such as fluo-4. The supernatant is added to the well, and a change influorescence is detected.

To measure the fluorescence of intracellular calcium, the FLIPR is setfor the following parameters: (1) System gain is 300-800 mW; (2)Exposure time is 0.4 second; (3) Camera F/stop is F/2; (4) Excitation is488 nm; (5) Emission is 530 nm; and (6) Sample addition is 50 ul.Increased emission at 530 nm indicates an extracellular signaling eventcaused by the a molecule, either polypeptide of the present invention ora molecule induced by polypeptide of the present invention, which hasresulted in an increase in the intracellular Ca⁺⁺ concentration.

Example 29 High-Throughput Screening Assay Identifying Tyrosine KinaseActivity

The Protein Tyrosine Kinases (PTK) represent a diverse group oftransmembrane and cytoplasmic kinases. Within the Receptor ProteinTyrosine Kinase RPTK) group are receptors for a range of mitogenic andmetabolic growth factors including the PDGF, FGF, EGF, NGF, HGF andInsulin receptor subfamilies. In addition there are a large family ofRPTKs for which the corresponding ligand is unknown. Ligands for RPTKsinclude mainly secreted small proteins, but also membrane-bound andextracellular matrix proteins.

Activation of RPTK by ligands involves ligand-mediated receptordimerization, resulting in transphosphorylation of the receptor subunitsand activation of the cytoplasmic tyrosine kinases. The cytoplasmictyrosine kinases include receptor associated tyrosine kinases of thesrc-family (e.g., src, yes, lck, lyn, fyn) and non-receptor linked andcytosolic protein tyrosine kinases, such as the Jak family, members ofwhich mediate signal transduction triggered by the cytokine superfamilyof receptors (e.g., the Interleukins, Interferons, GM-CSF, and Leptin).

Because of the wide range of known factors capable of stimulatingtyrosine kinase activity, identifying whether polypeptide of the presentinvention or a molecule induced by polypeptide of the present inventionis capable of activating tyrosine kinase signal transduction pathways isof interest. Therefore, the following protocol is designed to identifysuch molecules capable of activating the tyrosine kinase signaltransduction pathways.

Seed target cells (e.g., primary keratinocytes) at a density ofapproximately 25,000 cells per well in a 96 well Loprodyne Silent ScreenPlates purchased from Nalge Nunc (Naperville, Ill.). The plates aresterilized with two 30 minute rinses with 100% ethanol, rinsed withwater and dried overnight. Some plates are coated for 2 hr with 100 mlof cell culture grade type I collagen (50 mg/ml), gelatin (2%) orpolylysine (50 mg/ml), all of which can be purchased from SigmaChemicals (St. Louis, Mo.) or 10% Matrigel purchased from BectonDickinson (Bedford, Mass.), or calf serum, rinsed with PBS and stored at4 degree C. Cell growth on these plates is assayed by seeding 5,000cells/well in growth medium and indirect quantitation of cell numberthrough use of alamarBlue as described by the manufacturer AlamarBiosciences, Inc. (Sacramento, Calif.) after 48 hr. Falcon plate covers#3071 from Becton Dickinson (Bedford, Mass.) are used to cover theLoprodyne Silent Screen Plates. Falcon Microtest III cell culture platescan also be used in some proliferation experiments.

To prepare extracts, A431 cells are seeded onto the nylon membranes ofLoprodyne plates (20,000/200 ml/well) and cultured overnight in completemedium. Cells are quiesced by incubation in serum-free basal medium for24 hr. After 5-20 minutes treatment with EGF (60 ng/ml) or 50 ul of thesupernatant produced in Example 25, the medium was removed and 100 ml ofextraction buffer ((20 mM HEPES pH 7.5, 0.15 M NaCl, 1% Triton X-100,0.1% SDS, 2 mM Na3VO4, 2 mM Na4P207 and a cocktail of proteaseinhibitors (# 1836170) obtained from Boeheringer Mannheim (Indianapolis,Ind.)) is added to each well and the plate is shaken on a rotatingshaker for 5 minutes at 4° C. The plate is then placed in a vacuumtransfer manifold and the extract filtered through the 0.45 mm membranebottoms of each well using house vacuum. Extracts are collected in a96-well catch/assay plate in the bottom of the vacuum manifold andimmediately placed on ice. To obtain extracts clarified bycentrifugation, the content of each well, after detergent solubilizationfor 5 minutes, is removed and centrifuged for 15 minutes at 4 degree Cat16,000×g.

Test the filtered extracts for levels of tyrosine kinase activity.Although many methods of detecting tyrosine kinase activity are known,one method is described here.

Generally, the tyrosine kinase activity of a supernatant is evaluated bydetermining its ability to phosphorylate a tyrosine residue on aspecific substrate (a biotinylated peptide). Biotinylated peptides thatcan be used for this purpose include PSK1 (corresponding to amino acids6-20 of the cell division kinase cdc2-p34) and PSK2 (corresponding toamino acids 1-17 of gastrin). Both peptides are substrates for a rangeof tyrosine kinases and are available from Boehringer Mannheim

The tyrosine kinase reaction is set up by adding the followingcomponents in order. First, add 10 ul of 5 uM Biotinylated Peptide, then10 ul ATP/Mg₂₊ (5 mM ATP/50 mM MgCl₂), then 10 ul of 5× Assay Buffer (40mM imidazole hydrochloride, pH7.3, 40 mM beta-glycerophosphate, 1 mMEGTA, 100 mM MgCl₂, 5 mM MnCl₂, 0.5 mg/ml BSA), then 5 ul of SodiumVanadate(1 mM), and then 5 ul of water. Mix the components gently andpreincubate the reaction mix at 30 degree C. for 2 min. Initial thereaction by adding 10 ul of the control enzyme or the filteredsupernatant.

The tyrosine kinase assay reaction is then terminated by adding 10 ul of120 mm EDTA and place the reactions on ice.

Tyrosine kinase activity is determined by transferring 50 ul aliquot ofreaction mixture to a microtiter plate (MTP) module and incubating at 37degree C. for 20 min. This allows the streptavidin coated 96 well plateto associate with the biotinylated peptide. Wash the MTP module with 300ul/well of PBS four times. Next add 75 ul of anti-phospotyrosineantibody conjugated to horse radish peroxidase(anti-P-Tyr-POD(0.5 u/ml))to each well and incubate at 37 degree C. for one hour. Wash the well asabove.

Next add 100 ul of peroxidase substrate solution (Boehringer Mannheim)and incubate at room temperature for at least 5 mins (up to 30 min).Measure the absorbance of the sample at 405 nm by using ELISA reader.The level of bound peroxidase activity is quantitated using an ELISAreader and reflects the level of tyrosine kinase activity.

Example 30 High-Throughput Screening Assay Identifying PhosphorylationActivity

As a potential alternative and/or complement to the assay of proteintyrosine kinase activity described in Example 29, an assay which detectsactivation (phosphorylation) of major intracellular signal transductionintermediates can also be used. For example, as described below oneparticular assay can detect tyrosine phosphorylation of the Erk-1 andErk-2 kinases. However, phosphorylation of other molecules, such as Raf,JNK, p38 MAP, Map kinase kinase (MEK), MEK kinase, Src, Muscle specifickinase (MuSK), IRAK, Tec, and Janus, as well as any other phosphoserine,phosphotyrosine, or phosphothreonine molecule, can be detected bysubstituting these molecules for Erk-1 or Erk-2 in the following assay.

Specifically, assay plates are made by coating the wells of a 96-wellELISA plate with 0.1 ml of protein G (1 ug/ml) for 2 hr at room temp,(RT). The plates are then rinsed with PBS and blocked with 3% BSA/PBSfor 1 hr at RT. The protein G plates are then treated with 2 commercialmonoclonal antibodies (100 ng/well) against Erk-1 and Erk-2 (1 hr at RT)(Santa Cruz Biotechnology). (To detect other molecules, this step caneasily be modified by substituting a monoclonal antibody detecting anyof the above described molecules.) After 3-5 rinses with PBS, the platesare stored at 4 degree C. until use.

A431 cells are seeded at 20,000/well in a 96-well Loprodyne filterplateand cultured overnight in growth medium. The cells are then starved for48 hr in basal medium (DM and then treated with EGF (6 ng/well) or 50 ulof the supernatants obtained in Example 25 for 5-20 minutes. The cellsare then solubilized and extracts filtered directly into the assayplate.

After incubation with the extract for 1 hr at RT, the wells are againrinsed. As a positive control, a commercial preparation of MAP kinase(10 ng/well) is used in place of A431 extract. Plates are then treatedwith a commercial polyclonal (rabbit) antibody (lug/ml) whichspecifically recognizes the phosphorylated epitope of the Erk-1 andErk-2 kinases (1 hr at RT). This antibody is biotinylated by standardprocedures. The bound polyclonal antibody is then quantitated bysuccessive incubations with Europium-streptavidin and Europiumfluorescence enhancing reagent in the Wallac DELFIA instrument(time-resolved fluorescence). An increased fluorescent signal overbackground indicates a phosphorylation by polypeptide of the presentinvention or a molecule induced by polypeptide of the present invention.

Example 31 Human Dermal Fibroblast and Aortic Smooth Muscle CellProliferation

The polypeptide of interest is added to cultures of normal human dermalfibroblasts (NHDF) and human aortic smooth muscle cells (AoSMC) and twoco-assays are performed with each sample. The first assay examines theeffect of the polypeptide of interest on the proliferation of normalhuman dermal fibroblasts (NHDF) or aortic smooth muscle cells (AoSMC).Aberrant growth of fibroblasts or smooth muscle cells is a part ofseveral pathological processes, including fibrosis, and restenosis. Thesecond assay examines IL6 production by both NHDF and SMC. IL6production is an indication of functional activation. Activated cellswill have increased production of a number of cytokines and otherfactors, which can result in a proinflammatory or immunomodulatoryoutcome. Assays are run with and without co-TNFa stimulation, in orderto check for costimulatory or inhibitory activity.

Briefly, on day 1, 96-well black plates are set up with 1000 cells/well(NHDF) or 2000 cells/well (AoSMC) in 100 μl culture media. NHDF culturemedia contains: Clonetics FB basal media, 1 mg/ml hFGF, 5 mg/ml insulin,50 mg/ml gentamycin, 2% FBS, while AoSMC culture media containsClonetics SM basal media, 0.5 μg/ml hEGF, 5 mg/ml insulin, 1 μg/milhFGF, 50 mg/ml gentamycin, 50 μg/ml Amphotericin B, 5% FBS. Afterincubation at 37° C. for at least 4-5 hours culture media is aspiratedand replaced with growth arrest media. Growth arrest media for NHDFcontains fibroblast basal media, 50 mg/ml gentamycin, 2% FBS, whilegrowth arrest media for AoSMC contains SM basal media, 50 mg/mlgentamycin, 50 μg/ml Amphotericin B, 0.4% FBS. Incubate at 37° C. untilday 2.

On day 2, serial dilutions and templates of the polypeptide of interestare designed such that they always include media controls andknown-protein controls. For both stimulation and inhibition experiments,proteins are diluted in growth arrest media. For inhibition experiments,TNFa is added to a final concentration of 2 ng/ml (NHDF) or 5 ng/ml(AoSMC). Add ⅓ vol media containing controls or polypeptides of thepresent invention and incubate at 37 degrees C./5% CO₂ until day 5.

Transfer 60 μl from each well to another labeled 96-well plate, coverwith a plate-sealer, and store at 4 degrees C. until Day 6 (for EL6ELISA). To the remaining 100 μl in the cell culture plate, asepticallyadd Alamar Blue in an amount equal to 10% of the culture volume (10 μl).Return plates to incubator for 3 to 4 hours. Then measure fluorescencewith excitation at 530 nm and emission at 590 nm using the CytoFluor.This yields the growth stimulation/inhibition data.

On day 5, the IL6 ELISA is performed by coating a 96 well plate with50-100 ul/well of Anti-Human IL6 Monoclonal antibody diluted in PBS, pH7.4, incubate ON at room temperature.

On day 6, empty the plates into the sink and blot on paper towels.Prepare Assay Buffer containing PBS with 4% BSA. Block the plates with200 μl/well of Pierce Super Block blocking buffer in PBS for 1-2 hr andthen wash plates with wash buffer (PBS, 0.05% Tween-20). Blot plates onpaper towels. Then add 50 μl/well of diluted Anti-Human IL-6 Monoclonal,Biotin-labeled antibody at 0.50 mg/ml. Make dilutions of IL-6 stock inmedia (30, 10, 3, 1, 0.3, 0 ng/ml). Add duplicate samples to top row ofplate. Cover the plates and incubate for 2 hours at RT on shaker.

Plates are washed with wash buffer and blotted on paper towels. DiluteEU-labeled Streptavidin 1:1000 in Assay buffer, and add 100 μl/well.Cover the plate and incubate 1 h at RT. Plates are again washed withwash buffer and blotted on paper towels.

Add 100 μl/well of Enhancement Solution. Shake for 5 minutes. Read theplate on the Wallac DELFIA Fluorometer. Readings from triplicate samplesin each assay were tabulated and averaged.

A positive result in this assay suggests AoSMC cell proliferation andthat the polypeptide of the present invention may be involved in dermalfibroblast proliferation and/or smooth muscle cell proliferation. Apositive result also suggests many potential uses of polypeptides,polynucleotides, agonists and/or antagonists of thepolynucleotide/polypeptide of the present invention which gives apositive result. For example, inflammation and immune responses, woundhealing, and angiogenesis, as detailed throughout this specification.Particularly, polypeptides of the present invention and polynucleotidesof the present invention may be used in wound healing and dermalregeneration, as well as the promotion of vasculogenesis, both of theblood vessels and lymphatics. The growth of vessels can be used in thetreatment of, for example, cardiovascular diseases. Additionally,antagonists of polypeptides and polynucleotides of the invention may beuseful in treating diseases, disorders, and/or conditions which involveangiogenesis by acting as an anti-vascular agent (e.g.,anti-angiogenesis). These diseases, disorders, and/or conditions areknown in the art and/or are described herein, such as, for example,malignancies, solid tumors, benign tumors, for example hemangiomas,acoustic neuromas, neurofibromas, trachomas, and pyogenic granulomas;artheroscleric plaques; ocular angiogenic diseases, for example,diabetic retinopathy, retinopathy of prematurity, macular degeneration,corneal graft rejection, neovascular glaucoma, retrolental fibroplasia,rubeosis, retinoblastoma, uvietis and Pterygia (abnormal blood vesselgrowth) of the eye; rheumatoid arthritis; psoriasis; delayed woundhealing; endometriosis; vasculogenesis; granulations; hypertrophic scars(keloids); nonunion fractures; scleroderma; trachoma; vascularadhesions; myocardial angiogenesis; coronary collaterals; cerebralcollaterals; arteriovenous malformations; ischemic limb angiogenesis;Osler-Webber Syndrome; plaque neovascularization; telangiectasia;hemophiliac joints; angiofibroma; fibromuscular dysplasia; woundgranulation; Crohn's disease; and atherosclerosis. Moreover, antagonistsof polypeptides and polynucleotides of the invention may be useful intreating anti-hyperproliferative diseases and/or anti-inflammatory knownin the art and/or described herein.

One skilled in the art could easily modify the exemplified studies totest the activity of polynucleotides (e.g., gene therapy), antibodies,agonists, and/or antagonists and fragments and variants thereof.

Example 32 Cellular Adhesion Molecule (CAM) Expression on EndothelialCells

The recruitment of lymphocytes to areas of inflammation and angiogenesisinvolves specific receptor-ligand interactions between cell surfaceadhesion molecules (CAMs) on lymphocytes and the vascular endothelium.The adhesion process, in both normal and pathological settings, followsa multi-step cascade that involves intercellular adhesion molecule-1(ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and endothelialleukocyte adhesion molecule-1 (E-selectin) expression on endothelialcells (EC). The expression of these molecules and others on the vascularendothelium determines the efficiency with which leukocytes may adhereto the local vasculature and extravasate into the local tissue duringthe development of an inflammatory response. The local concentration ofcytokines and growth factor participate in the modulation of theexpression of these CAMs.

Briefly, endothelial cells (e.g., Human Umbilical Vein Endothelial cells(HUVECs)) are grown in a standard 96 well plate to confluence, growthmedium is removed from the cells and replaced with 100 μl of 199 Medium(10% fetal bovine serum (PBS)). Samples for testing and positive ornegative controls are added to the plate in triplicate (in 10 μlvolumes). Plates are then incubated at 37° C. for either 5 h (selectinand integrin expression) or 24 h (integrin expression only). Plates areaspirated to remove medium and 100 μl of 0.1% paraformaldehyde-PBS (withCa++ and Mg++) is added to each well. Plates are held at 4° C. for 30min. Fixative is removed from the wells and wells are washed 1× with PBS(+Ca,Mg)+0.5% BSA and drained. 10 μl of diluted primary antibody isadded to the test and control wells. Anti-ICAM-1-Biotin,Anti-VCAM-1-Biotin and Anti-E-selectin-Biotin are used at aconcentration of 10 μg/ml (1:10 dilution of 0.1 mg/ml stock antibody).Cells are incubated at 37° C. for 30 min. in a humidified environment.Wells are washed three times with PBS(+Ca,Mg)+0.5% BSA. 20 μl of dilutedExtrAvidin-Alkaline Phosphatase (1:5,000 dilution, referred to herein asthe working dilution) are added to each well and incubated at 37° C. for30 min. Wells are washed three times with PBS(+Ca,Mg)+0.5% BSA. Dissolve1 tablet of p-Nitrophenol Phosphate pNPP per 5 ml of glycine buffer (pH10.4). 100 μl of pNPP substrate in glycine buffer is added to each testwell. Standard wells in triplicate are prepared from the workingdilution of the ExtrAvidin-Alkaline Phosphotase in glycine buffer:1:5,000 (10⁰)>10^(−0.5)>10⁻¹>10^(−1.5).5 μl of each dilution is added totriplicate wells and the resulting AP content in each well is 5.50 ng,1.74 ng, 0.55 ng, 0.18 ng. 100 μl of pNNP reagent is then added to eachof the standard wells. The plate is incubated at 37° C. for 4 h. Avolume of 50 μl of 3M NaOH is added to all wells. The plate is read on aplate reader at 405 nm using the background subtraction option on blankwells filled with glycine buffer only. Additionally, the template is setup to indicate the concentration of AP-conjugate in each standard well[5.50 ng; 1.74 ng; 0.55 ng; 0.18 ng]. Results are indicated as amount ofbound AP-conjugate in each sample.

Example 33 Alamar Blue Endothelial Cells Proliferation Assay

This assay may be used to quantitatively determine protein mediatedinhibition of bFGF-induced proliferation of Bovine Lymphatic EndothelialCells (LECs), Bovine Aortic Endothelial Cells (BAECs) or HumanMicrovascular Uterine Myometrial Cells (UTMECs). This assay incorporatesa fluorometric growth indicator based on detection of metabolicactivity. A standard Alamar Blue Proliferation Assay is prepared inEGM-2MV with 10 ng/ml of bFGF added as a source of endothelial cellstimulation. This assay may be used with a variety of endothelial cellswith slight changes in growth medium and cell concentration. Dilutionsof the protein batches to be tested are diluted as appropriate.Serum-free medium (GIBCO SFM) without bFGF is used as a non-stimulatedcontrol and Angiostatin or TSP-1 are included as a known inhibitorycontrols.

Briefly, LEC, BAECs or UTMECs are seeded in growth media at a density of5000 to 2000 cells/well in a 96 well plate and placed at 37 degrees Covernight. After the overnight incubation of the cells, the growth mediais removed and replaced with GIBCO EC-SFM. The cells are treated withthe appropriate dilutions of the protein of interest or control proteinsample(s) (prepared in SFM) in triplicate wells with additional bFGF toa concentration of 10 ng/ml. Once the cells have been treated with thesamples, the plate(s) is/are placed back in the 37° C. incubator forthree days. After three days 10 ml of stock alamar blue (Biosource Cat#DAL 100) is added to each well and the plate(s) is/are placed back inthe 37° C. incubator for four hours. The plate(s) are then read at 530nm excitation and 590 nm emission using the CytoFluor fluorescencereader. Direct output is recorded in relative fluorescence units.

Alamar blue is an oxidation-reduction indicator that both fluoresces andchanges color in response to chemical reduction of growth mediumresulting from cell growth. As cells grow in culture, innate metabolicactivity results in a chemical reduction of the immediate surroundingenvironment. Reduction related to growth causes the indicator to changefrom oxidized (non-fluorescent blue) form to reduced (fluorescent red)form (i.e., stimulated proliferation will produce a stronger signal andinhibited proliferation will produce a weaker signal and the totalsignal is proportional to the total number of cells as well as theirmetabolic activity). The background level of activity is observed withthe starvation medium alone. This is compared to the output observedfrom the positive control samples (bFGF in growth medium) and proteindilutions.

Example 34 Detection of Inhibition of a Mixed Lymphocyte Reaction

This assay can be used to detect and evaluate inhibition of a MixedLymphocyte Reaction (MLR) by gene products (e.g., isolatedpolypeptides). Inhibition of a MLR may be due to a direct effect on cellproliferation and viability, modulation of costimulatory molecules oninteracting cells, modulation of adhesiveness between lymphocytes andaccessory cells, or modulation of cytokine production by accessorycells. Multiple cells may be targeted by these polypeptides since theperipheral blood mononuclear fraction used in this assay includes T, Band natural killer lymphocytes, as well as monocytes and dendriticcells.

Polypeptides of interest found to inhibit the MLR may find applicationin diseases associated with lymphocyte and monocyte activation orproliferation. These include, but are not limited to, diseases such asasthma, arthritis, diabetes, inflammatory skin conditions, psoriasis,eczema, systemic lupus erythematosus, multiple sclerosis,glomerulonephritis, inflammatory bowel disease, crohn's disease,ulcerative colitis, arteriosclerosis, cirrhosis, graft vs. host disease,host vs. graft disease, hepatitis, leukemia and lymphoma.

Briefly, PBMCs from human donors are purified by density gradientcentrifugation using Lymphocyte Separation Medium (LSM®, density 1.0770g/ml, Organon Teknika Corporation, West Chester, Pa.). PBMCs from twodonors are adjusted to 2×10⁶ cells/ml in RPMI-1640 (Life Technologies,Grand Island, N.Y.) supplemented with 10% FCS and 2 mM glutamine. PBMCsfrom a third donor is adjusted to 2×10⁵ cells/ml. Fifty microliters ofPBMCs from each donor is added to wells of a 96-well round bottommicrotiter plate. Dilutions of test materials (50 μl) is added intriplicate to microtiter wells. Test samples (of the protein ofinterest) are added for final dilution of 1:4; rhuIL-2 (R&D Systems,Minneapolis, Minn., catalog number 202-IL) is added to a finalconcentration of 1 μg/1 ml; anti-CD4 mAb (R&D Systems, clone 34930.11,catalog number MAB379) is added to a final concentration of 10 μg/pal.Cells are cultured for 7-8 days at 37° C. in 5% CO₂, and 1 μC of [³H]thymidine is added to wells for the last 16 hrs of culture. Cells areharvested and thymidine incorporation determined using a PackardTopCount. Data is expressed as the mean and standard deviation oftriplicate determinations.

Samples of the protein of interest are screened in separate experimentsand compared to the negative control treatment, anti-CD4 mAb, whichinhibits proliferation of lymphocytes and the positive controltreatment, IL-2 (either as recombinant material or supernatant), whichenhances proliferation of lymphocytes.

One skilled in the art could easily modify the exemplified studies totest the activity of polynucleotides (e.g., gene therapy), antibodies,agonists, and/or antagonists and fragments and variants thereof.

Example 35 Assays for Protease Activity

The following assay may be used to assess protease activity of thepolypeptides of the invention.

Gelatin and casein zymography are performed essentially as described(Heusen et al., Anal. Biochem, 102:196-202 (1980); Wilson et al.,Journal of Urology, 149:653-658 (1993)). Samples are run on 10%polyacryamide/0.1% SDS gels containing 1% gelain orcasein, soaked in2.5% triton at room temperature for 1 hour, and in 0.1M glycine, pH 8.3at 37° C. 5 to 16 hours. After staining in amido black areas ofproteolysis apear as clear areas agains the blue-black background.Trypsin (Sigma T8642) is used as a positive control.

Protease activity is also determined by monitoring the cleavage ofn-a-benzoyl-L-arginine ethyl ester (BAEE) (Sigma B4500. Reactions areset up in (25 mM NaPO₄, 1 mM EDTA, and 1 mM BAEE), pH 7.5. Samples areadded and the change in adsorbance at 260 nm is monitored on the BeckmanDUN spectrophotometer in the time-drive mode. Trypsin is used as apositive control.

Additional assays based upon the release of acid-soluble peptides fromcasein or hemoglobin measured as adsorbance at 280 nm orcolorimetrically using the Folin method are performed as described inBergmeyer, et al., Methods of Enzymatic Analysis, 5 (1984). Other assaysinvolve the solubilization of chromogenic substrates (Ward, AppliedScience, 251-317 (1983)).

Example 36 Identifying Serine Protease Substrate Specificity

Methods known in the art or described herein may be used to determinethe substrate specificity of the polypeptides of the present inventionhaving serine protease activity. A preferred method of determiningsubstrate specificity is by the use of positional scanning syntheticcombinatorial libraries as described in GB 2 324 529 (incorporatedherein in its entirety).

Example 37 Ligand Binding Assays

The following assay may be used to assess ligand binding activity of thepolypeptides of the invention.

Ligand binding assays provide a direct method for ascertaining receptorpharmacology and are adaptable to a high throughput format. The purifiedligand for a polypeptide is radiolabeled to high specific activity(50-2000 Ci/mmol) for binding studies. A determination is then made thatthe process of radiolabeling does not diminish the activity of theligand towards its polypeptide. Assay conditions for buffers, ions, pHand other modulators such as nucleotides are optimized to establish aworkable signal to noise ratio for both membrane and whole cellpolypeptide sources. For these assays, specific polypeptide binding isdefined as total associated radioactivity minus the radioactivitymeasured in the presence of an excess of unlabeled competing ligand.Where possible, more than one competing ligand is used to defineresidual nonspecific binding.

Example 38 Functional Assay in Xenopus Oocytes

Capped RNA transcripts from linearized plasmid templates encoding thepolypeptides of the invention are synthesized in vitro with RNApolymerases in accordance with standard procedures. In vitro transcriptsare suspended in water at a final concentration of 0.2 mg/ml. Ovarianlobes are removed from adult female toads, Stage V defolliculatedoocytes are obtained, and RNA transcripts (10 ng/oocytc) are injected ina 50 nl bolus using a microinjection apparatus. Two electrode voltageclamps are used to measure the currents from individual Xenopus oocytesin response polypeptides and polypeptide agonist exposure. Recordingsare made in Ca2+ free Barth's medium at room temperature. The Xenopussystem can be used to screen known ligands and tissue/cell extracts foractivating ligands.

Example 39 Microphysiometric Assays

Activation of a wide variety of secondary messenger systems results inextrusion of small amounts of acid from a cell. The acid formed islargely as a result of the increased metabolic activity required to fuelthe intracellular signaling process. The pH changes in the mediasurrounding the cell are very small but are detectable by the CYTOSENSORmicrophysiometer (Molecular Devices Ltd., Menlo Park, Calif.). TheCYTOSENSOR is thus capable of detecting the activation of polypeptidewhich is coupled to an energy utilizing intracellular signaling pathway.

Example 40 Extract/Cell Supernatant Screening

A large number of mammalian receptors exist for which there remains, asyet, no cognate activating ligand (agonist). Thus, active ligands forthese receptors may not be included within the ligands banks asidentified to date. Accordingly, the polypeptides of the invention canalso be functionally screened (using calcium, cAMP, microphysiometer,oocyte electrophysiology, etc., functional screens) against tissueextracts to identify its natural ligands. Extracts that produce positivefunctional responses can be sequentially subfractionated until anactivating ligand is isolated and identified.

Example 41 Calcium and cAMP Functional Assays

Seven transmembrane receptors which are expressed in HEK 293 cells havebeen shown to be coupled functionally to activation of PLC and calciummobilization and/or cAMP stimulation or inhibition. Basal calcium levelsin the HEK 293 cells in receptor-transfected or vector control cellswere observed to be in the normal, 100 nM to 200 nM, range. HEK 293cells expressing recombinant receptors are loaded with fura 2 and in asingle day >150 selected ligands or tissue/cell extracts are evaluatedfor agonist induced calcium mobilization. Similarly, HEK 293 cellsexpressing recombinant receptors are evaluated for the stimulation orinhibition of cAMP production using standard cAMP quantitation assays.Agonists presenting a calcium transient or cAMP fluctuation are testedin vector control cells to determine if the response is unique to thetransfected cells expressing receptor.

Example 42 ATP-binding Assay

The following assay may be used to assess ATP-binding activity ofpolypeptides of the invention.

ATP-binding activity of the polypeptides of the invention may bedetected using the ATP-binding assay described in U.S. Pat. No.5,858,719, which is herein incorporated by reference in its entirety.Briefly, ATP-binding to polypeptides of the invention is measured viaphotoaffinity labeling with 8-azido-ATP in a competition assay. Reactionmixtures containing 1 mg/ml of the ABC transport protein of the presentinvention are incubated with varying concentrations of ATP, or thenon-hydrolyzable ATP analog adenyl-5′-imidodiphosphate for 10 minutes at4° C. A mixture of 8-azido-ATP (Sigma Chem. Corp., St. Louis, Mo.) plus8-azido-ATP (³²P-ATP) (5 mCi/μmol, ICN, Irvine Calif.) is added to afinal concentration of 100 P and 0.5 ml aliquots are placed in the wellsof a porcelain spot plate on ice. The plate is irradiated using a shortwave 254 nm UV lamp at a distance of 2.5 cm from the plate for twoone-minute intervals with a one-minute cooling interval in between. Thereaction is stopped by addition of dithiothreitol to a finalconcentration of 2 mM. The incubations are subjected to SDS-PAGEelectrophoresis, dried, and autoradiographed. Protein bandscorresponding to the particular polypeptides of the invention areexcised, and the radioactivity quantified. A decrease in radioactivitywith increasing ATP or adenly-5′-imidodiphosphate provides a measure ofATP affinity to the polypeptides.

Example 43 Small Molecule Screening

This invention is particularly useful for screening therapeuticcompounds by using the polypeptides of the invention, or bindingfragments thereof, in any of a variety of drug screening techniques. Thepolypeptide or fragment employed in such a test may be affixed to asolid support, expressed on a cell surface, free in solution, or locatedintracellularly. One method of drug screening utilizes eukaryotic orprokaryotic host cells which are stably transformed with recombinantnucleic acids expressing the polypeptide or fragment. Drugs are screenedagainst such transformed cells in competitive binding assays. One maymeasure, for example, the formulation of complexes between the agentbeing tested and polypeptide of the invention.

Thus, the present invention provides methods of screening for drugs orany other agents which affect activities mediated by the polypeptides ofthe invention. These methods comprise contacting such an agent with apolypeptide of the invention or fragment thereof and assaying for thepresence of a complex between the agent and the polypeptide or fragmentthereof, by methods well known in the art. In such a competitive bindingassay, the agents to screen are typically labeled. Following incubation,free agent is separated from that present in bound form, and the amountof free or uncomplexed label is a measure of the ability of a particularagent to bind to the polypeptides of the invention.

Another technique for drug screening provides high throughput screeningfor compounds having suitable binding affinity to the polypeptides ofthe invention, and is described in great detail in European PatentApplication 84103564, published on Sep. 13, 1984, which is hereinincorporated by reference in its entirety. Briefly stated, large numbersof different small molecule test compounds are synthesized on a solidsubstrate, such as plastic pins or some other surface. The testcompounds are reacted with polypeptides of the invention and washed.Bound polypeptides are then detected by methods well known in the art.Purified polypeptides are coated directly onto plates for use in theaforementioned drug screening techniques. In addition, non-neutralizingantibodies may be used to capture the peptide and immobilize it on thesolid support.

This invention also contemplates the use of competitive drug screeningassays in which neutralizing antibodies capable of binding polypeptidesof the invention specifically compete with a test compound for bindingto the polypeptides or fragments thereof. In this manner, the antibodiesare used to detect the presence of any peptide which shares one or moreantigenic epitopes with a polypeptide of the invention.

Example 44 Phosphorylation Assay

In order to assay for phosphorylation activity of the polypeptides ofthe invention, a phosphorylation assay as described in U.S. Pat. No.5,958,405 (which is herein incorporated by reference) is utilized.Briefly, phosphorylation activity may be measured by phosphorylation ofa protein substrate using gamma-labeled ³²P-ATP and quantitation of theincorporated radioactivity using a gamma radioisotope counter. Thepolypeptides of the invention are incubated with the protein substrate,³²P-ATP, and a kinase buffer. The ³²P incorporated into the substrate isthen separated from free ³²P-ATP by electrophoresis, and theincorporated ³²P is counted and compared to a negative control.Radioactivity counts above the negative control are indicative ofphosphorylation activity of the polypeptides of the invention.

Example 45 Detection of Phosphorylation Activity (Activation) of thePolypeptides of the Invention in the Presence of Polypeptide Ligands

Methods known in the art or described herein may be used to determinethe phosphorylation activity of the polypeptides of the invention. Apreferred method of determining phosphorylation activity is by the useof the tyrosine phosphorylation assay as described in U.S. Pat. No.5,817,471 (incorporated herein by reference).

Example 46 Identification Of Signal Transduction Proteins That InteractWith Polypeptides Of The Present Invention

The purified polypeptides of the invention are research tools for theidentification, characterization and purification of additional signaltransduction pathway proteins or receptor proteins. Briefly, labeledpolypeptides of the invention are useful as reagents for thepurification of molecules with which it interacts. In one embodiment ofaffinity purification, polypeptides of the invention are covalentlycoupled to a chromatography column. Cell-free extract derived fromputative target cells, such as carcinoma tissues, is passed over thecolumn, and molecules with appropriate affinity bind to the polypeptidesof the invention. The protein complex is recovered from the column,dissociated, and the recovered molecule subjected to N-terminal proteinsequencing. This amino acid sequence is then used to identify thecaptured molecule or to design degenerate oligonucleotide probes forcloning the relevant gene from an appropriate cDNA library.

Example 47 Assay for Phosphatase Activity

The following assay may be used to assess serine/threonine phosphatase(PTPase) activity of the polypeptides of the invention.

In order to assay for serine/threonine phosphatase (PTPase) activity,assays can be utilized which are widely known to those skilled in theart. For example, the serine/threonine phosphatase (PSPase) activity ismeasured using a PSPase assay kit from New England Biolabs, Inc. Myelinbasic protein (MyBP), a substrate for PSPase, is phosphorylated onserine and threonine residues with cAMP-dependent Protein Kinase in thepresence of [³²P]ATP. Protein serine/threonine phosphatase activity isthen determined by measuring the release of inorganic phosphate from³²P-labeled MyBP.

Example 48 Interaction of Serine/Threonine Phosphatases with otherProteins

The polypeptides of the invention with serine/threonine phosphataseactivity as determined in Example 47 are research tools for theidentification, characterization and purification of additionalinteracting proteins or receptor proteins, or other signal transductionpathway proteins. Briefly, labeled polypeptide(s) of the invention isuseful as a reagent for the purification of molecules with which itinteracts. In one embodiment of affinity purification, polypeptide ofthe invention is covalently coupled to a chromatography column.Cell-free extract derived from putative target cells, such as neural orliver cells, is passed over the column, and molecules with appropriateaffinity bind to the polypeptides of the invention. The polypeptides ofthe invention-complex is recovered from the column, dissociated, and therecovered molecule subjected to N-terminal protein sequencing. Thisamino acid sequence is then used to identify the captured molecule or todesign degenerate oligonucleotide probes for cloning the relevant genefrom an appropriate cDNA library.

Example 49 Assaying for Heparanase Activity

In order to assay for heparanase activity of the polypeptides of theinvention, the heparanase assay described by Vlodavsky et al is utilized(Vlodavsky, L, et al., Nat. Med., 5:793-802 (1999)). Briefly, celllysates, conditioned media or intact cells (1×10⁶ cells per 35-mm dish)are incubated for 18 hrs at 37° C., pH 6.2-6.6, with ³⁵S-labeled ECM orsoluble ECM derived peak I proteoglycans. The incubation medium iscentrifuged and the supernatant is analyzed by gel filtration on aSepharose CL-6B column (0.9×30 cm). Fractions are eluted with PBS andtheir radioactivity is measured. Degradation fragments of heparansulfate side chains are eluted from Sepharose 6B at 0.5<K_(av)<0.8 (peakII). Each experiment is done at least three times. Degradation fragmentscorresponding to “peak II,” as described by Vlodavsky et al., isindicative of the activity of the polypeptides of the invention incleaving heparan sulfate.

Example 50 Immobilization of Biomolecules

This example provides a method for the stabilization of polypeptides ofthe invention in non-host cell lipid bilayer constucts (see, e.g., Bieriet al., Nature Biotech 17:1105-1108 (1999), hereby incorporated byreference in its entirety herein) which can be adapted for the study ofpolypeptides of the invention in the various functional assays describedabove. Briefly, carbohydrate-specific chemistry for biotinylation isused to confine a biotin tag to the extracellular domain of thepolypeptides of the invention, thus allowing uniform orientation uponimmobilization. A 50 uM solution of polypeptides of the invention inwashed membranes is incubated with 20 mM NaIO4 and 1.5 mg/ml (4 mM) BACHor 2 mg/ml (7.5 mM) biotin-hydrazide for 1 hr at room temperature(reaction volume, 150 ul). Then the sample is dialyzed (PierceSlidealizer Cassett, 10 kDa cutoff; Pierce Chemical Co., Rockford Ill.)at 4C first for 5 h, exchanging the buffer after each hour, and finallyfor 12 h against 500 ml buffer R (0.15 M NaCl, 1 mM MgCl2, 10 mM sodiumphosphate, pH7). Just before addition into a cuvette, the sample isdiluted 1:5 in buffer ROG50 (Buffer R supplemented with 50 mMoctylglucoside).

Example 51 TAQMAN

Quantitative PCR (QPCR). Total RNA from cells in culture are extractedby Trizol separation as recommended by the supplier (LifeTechnologies).(Total RNA is treated with DNase I (Life Technologies) to remove anycontaminating genomic DNA before reverse transcription.) Total RNA (50ng) is used in a one-step, 50 ul, RT-QPCR, consisting of Taqman Buffer A(Perkin-Elmer; 50 mM KCl/10 mM Tris, pH 8.3), 5.5 mM MgCl₂, 240 μM eachdNTP, 0.4 units RNase inhibitor(Promega), 8% glycerol, 0.012% Tween-20,0.05% gelatin, 0.3 uM primers, 0.1 uM probe, 0.025 units Amplitaq Gold(Perkin-Elmer) and 2.5 units Superscript II reverse transcriptase (LifeTechnologies). As a control for genomic contamination, parallelreactions are setup without reverse transcriptase. The relativeabundance of (unknown) and 18S RNAs are assessed by using the AppliedBiosystems Prism 7700 Sequence Detection System (Livak, K. J., Flood, S.J., Marnaro, J., Giusti, W. & Deetz, K. (1995) PCR Methods Appl. 4,357-362). Reactions are carried out at 48° C. for 30 min, 95° C. for 10min, followed by 40 cycles of 95° C. for 15 s, 60° C. for 1 min.Reactions are performed in triplicate.

Primers (f & r) and FRET probes sets are designed using Primer ExpressSoftware (Perkin-Elmer). Probes are labeled at the 5′-end with thereporter dye 6-FAM and on the 3′-end with the quencher dye TAMRA(Biosource International, Camarillo, Calif. or Perkin-Elmer).

Example 52 Assays for Metalloproteinase Activity

Metalloproteinases (EC 3.4.24.−) are peptide hydrolases which use metalions, such as Zn²⁺, as the catalytic mechanism Metalloproteinaseactivity of polypeptides of the present invention can be assayedaccording to the following methods.

Proteolysis of Alpha-2-Macroglobulin

To confirm protease activity, purified polypeptides of the invention aremixed with the substrate alpha-2-macroglobulin (0.2 unit/mil; BoehringerMannheim, Germany) in 1× assay buffer (50 mM HEPES, pH 7.5, 0.2 M NaCl,10 mM CaCl₂, 25 μM ZnCl₂ and 0.05% Brij-35) and incubated at 37° C. for1-5 days. Trypsin is used as positive control. Negative controls containonly alpha-2-macroglobulin in assay buffer. The samples are collectedand boiled in SDS-PAGE sample buffer containing 5% 2-mercaptoethanol for5-min, then loaded onto 8% SDS-polyacrylamide gel. After electrophoresisthe proteins are visualized by silver staining. Proteolysis is evidentby the appearance of lower molecular weight bands as compared to thenegative control.

Inhibition of Alpha-2-Macroglobulin Proteolysis by Inhibitors ofMetalloproteinases

Known metalloproteinase inhibitors (metal chelators (EDTA, EGTA, ANDHgCl₂), peptide metalloproteinase inhibitors (TIMP-1 and TIMP-2), andcommercial small molecule MMP inhibitors) are used to characterize theproteolytic activity of polypeptides of the invention. The threesynthetic MMP inhibitors used are: MMP inhibitor I, [IC₅₀=1.0 μM againstMMP-1 and MMP-8; IC₅₀=30 μM against MMP-9; IC₅₀=150 μM against MMP-3];MM-3 (stromelysin-1) inhibitor I [IC₅₀=5 μM against MMP-3], and MMP-3inhibitor II [K_(j)=130 nM against MMP-3]; inhibitors available throughCalbiochem, catalog #444250, 444218, and 444225, respectively). Briefly,different concentrations of the small molecule MMP inhibitors are mixedwith purified polypeptides of the invention (50 μg/1 ml) in 22.9 μl of1×HEPES buffer (50 mM HEPES, pH 7.5, 0.2 M NaCl, 10 mM CaCl₂, 25 μMZnCl₂ and 0.05% Brij-35) and incubated at room temperature (24° C.) for2-hr, then 7.1 μl of substrate alpha-2-macroglobulin (0.2 unit/ml) isadded and incubated at 37° C. for 20-hr. The reactions are stopped byadding 4× sample buffer and boiled immediately for 5 minutes. AfterSDS-PAGE, the protein bands are visualized by silver stain.

Synthetic Fluorogenic Peptide Substrates Cleavage Assay

The substrate specificity for polypeptides of the invention withdemonstrated metalloproteinase activity can be determined usingsynthetic fluorogenic peptide substrates (purchased from BACHEMBioscience Inc). Test substrates include, M-1985, M-2225, M-2105,M-2110, and M-2255. The first four are MMP substrates and the last oneis a substrate of tumor necrosis factors (TNF-a) converting enzyme(TACE). All the substrates are prepared in 1:1 dimethyl sulfoxide (DMSO)and water. The stock solutions are 50-500 μM. Fluorescent assays areperformed by using a Perkin Elmer LS 50B luminescence spectrometerequipped with a constant temperature water bath. The excitation λ is 328nm and the emission λ is 393 nm. Briefly, the assay is carried out byincubating 176 μl 1×HEPES buffer (0.2 M NaCl, 10 mM CaCl₂, 0.05% Brij-35and 50 mM HEPES, pH 7.5) with 4 μl of substrate solution (50 P) at 25°C. for 15 minutes, and then adding 20 μl of a purified polypeptide ofthe invention into the assay cuvett. The final concentration ofsubstrate is 1 μM. Initial hydrolysis rates are monitored for 30-min.

Example 53 Characterization of the cDNA Contained in a Deposited Plasmid

The size of the cDNA insert contained in a deposited plasmid may beroutinely determined using techniques known in the art, such as PCRamplification using synthetic primers hybridizable to the 3′ and 5′ endsof the cDNA sequence. For example, two primers of 17-30 nucleotidesderived from each end of the cDNA (i.e., hybridizable to the absolute 5′nucleotide or the 3′ nucleotide end of the sequence of SEQ ID NO:X,respectively) are synthesized and used to amplify the cDNA using thedeposited cDNA plasmid as a template. The polymerase chain reaction iscarried out under routine conditions, for instance, in 25 ul of reactionmixture with 0.5 ug of the above cDNA template. A convenient reactionmixture is 1.5-5 mM MgCl₂, 0.01% (w/v) gelatin, 20 uM each of dATP,dCTP, dGTP, dTTP, 25 pmol of each primer and 0.25 Unit of Taqpolymerase. Thirty five cycles of PCR (denaturation at 94 degree C. for1 min; annealing at 55 degree C. for 1 min; elongation at 72 degree C.for 1 min) are performed with a Perkin-Elmer Cetus automated thermalcycler. The amplified product is analyzed by agarose gelelectrophoresis. The PCR product is verified to be the selected sequenceby subcloning and sequencing the DNA product. It will be clear that theinvention may be practiced otherwise than as particularly described inthe foregoing description and examples. Numerous modifications andvariations of the present invention are possible in light of the aboveteachings and, therefore, are within the scope of the appended claims.

Incorporation by Reference

The entire disclosure of each document cited (including patents, patentapplications, journal articles, abstracts, laboratory manuals, books, orother disclosures) in the Background of the Invention, DetailedDescription, and Examples is hereby incorporated herein by reference. Inaddition, the sequence listing submitted herewith is incorporated hereinby reference in its entirety. The specification and sequence listing ofeach of the following U.S. and PCT applications are herein incorporatedby reference in their entirety (filing dates shown in format“year-month-day” (yyyy-mmn-dd)): Application No. 60/278,650 filed on2001 Mar. 27, application Ser. No. 09/950,082 filed on 2001 Sep. 12,application Ser. No. 09/950,083 filed on 2001 Sep. 12, Application No.60/306,171 filed on 19 Jul. 2001, application Ser. No. 09/833,245 filedon 2001 Apr. 12, Application No. PCT/US01/11988 filed on 2001 Apr. 12,Application No. 60/331,287 filed on 2001 Nov. 13, Application No.60/277,340 filed on 2001 Mar. 21, Application No. PCT/US00/06043 filedon 2000 Mar. 9, Application No. PCT/US00/06012 filed on 2000 Mar. 9,Application No. PCT/US00/06058 filed on 2000 Mar. 9, Application No.PCT/US00/06044 filed on 2000 Mar. 9, Application No. PCT/US00/06059filed on 2000 Mar. 9, Application No. PCT/US00/06042 filed on 2000 Mar.9, Application No. PCT/US00/06014 filed on 2000 Mar. 9, Application No.PCT/US00/06013 filed on 2000 Mar. 9, Application No. PCT/US00/06049filed on 2000 Mar. 9, Application No. PCT/US00/06057 filed on 2000 Mar.9, Application No. PC/US00/06824 filed on 2000 Mar. 16, Application No.PCT/US00/06765 filed on 2000 Mar. 16, Application No. PCT/US00/06792filed on 2000 Mar. 16, Application No. PCT/US00/06830 filed on 2000 Mar.16, Application No. PCT/US00/06782 filed on 2000 Mar. 16, ApplicationNo. PCT/US00/06822 filed on 2000 Mar. 16, Application No. PCT/US00/06791filed on 2000 Mar. 16, Application No. PCT/US00/06828 filed on 2000 Mar.16, Application No. PCT/US00/06823 filed on 2000 Mar. 16, ApplicationNo. PCT/US00/06781 filed on 2000 Mar. 16, Application No. PCT/US00/07505filed on 2000 Mar. 22, Application No. PCT/US00/07440 filed on 2000 Mar.22, Application No. PCT/US00/07506 filed on 2000 Mar. 22, ApplicationNo. PCT/US00/07507 filed on 2000 Mar. 22, Application No. PCT/US00/07535filed on 2000 Mar. 22, Application No. PCT/US00/07525 filed on 2000 Mar.22, Application No. PCT/US00/07534 filed on 2000 Mar. 22, ApplicationNo. PCT/US00/07483 filed on 2000 Mar. 22, Application No. PCT/US00/07526filed on 2000 Mar. 22, Application No. PCT/US00/07527 filed on 2000 Mar.22, Application No. PCT/US00/07661 filed on 2000 Mar. 23, ApplicationNo. PCT/US00/07579 filed on 2000 Mar. 23, Application No. PCT/US00/07723filed on 2000 Mar. 23, Application No. PCT/US00/07724 filed on 2000 Mar.23, Application No. PCT/US00/14929 filed on 2000 Jun. 1, Application No.PC/US00/07722 filed on 2000 Mar. 23, Application No. PCT/US00/07578filed on 2000 Mar. 23, Application No. PCT/US00/07726 filed on 2000 Mar.23, Application No. PCT/US00/07677 filed on 2000 Mar. 23, ApplicationNo. PCT/US00/07725 filed on 2000 Mar. 23, Application No. PCT/US00/09070filed on 2000 Apr. 6, Application No. PCT/US00/08982 filed on 2000 Apr.6, Application No. PCT/US00/08983 filed on 2000 Apr. 6, Application No.PCT/US00/09067 filed on 2000 Apr. 6, Application No. PCT/US00/09066filed on 2000 Apr. 6, Application No. PCT/US00/09068 filed on 2000 Apr.6, Application No. PCT/US00/08981 filed on 2000 Apr. 6, Application No.PCT/US00/08980 filed on 2000 Apr. 6, Application No. PCT/US0/09071 filedon 2000 Apr. 6, Application No. PCT/US00/09069 filed on 2000 Apr. 6,Application No. PCT/US00/15136 filed on 2000 Jun. 1, Application No.PCT/US00/14926 filed on 2000 Jun. 1, Application No. PCT/US00/14963filed on 2000 Jun. 1, Application No. PCT/US00/15135 filed on 2000 Jun.1, Application No. PCT/US00/14934 filed on 2000 Jun. 1, Application No.PCT/US00/14933 filed on 2000 Jun. 1, Application No. PCT/US00/15137filed on 2000 Jun. 1, Application. No. PCT/US00/14928 filed on 2000 Jun.1, Application No. PCT/US00/14973 filed on 2000 Jun. 1, Application No.PCT/US00/14964 filed on 2000406-01, Application No. PCT/US00/26376 filedon 2000 Sep. 26, Application No. PCT/US00/26371 filed on 2000 Sep. 26,Application No. PCT/US00/26324 filed on 2000 Sep. 26, Application No.PCT/US00/26323 filed on 2000 Sep. 26, Application No. PCT/US00/26337filed on 2000 Sep. 26, Application No. PCT/US01/13318 filed on 2001 Apr.27, Application No. U.S. 60/124,146 filed on 1999 Mar. 12, ApplicationNo. U.S. 60/167,061 filed on 1999 Nov. 23, Application No. U.S.60/124,093 filed on 1999 Mar. 12, Application No. U.S. 60/166,989 filedon 1999, Nov. 23, Application No. U.S. 60/124,145 filed on 1999 Mar. 12,Application No. U.S. 60/168,654 filed on 1999 Dec. 3, Application No.U.S. 60/124,099 filed on 1999 Mar. 12, Application No. U.S. 60/168,661filed on 1999 Dec. 3, Application No. U.S. 60/124,096 filed on 1999 Mar.12, Application No. U.S. 60/168,622 filed on 1999 Dec. 3, ApplicationNo. U.S. 60/124,143 filed on 1999 Mar. 12, Application No. U.S.60/168,663 filed on 1999 Dec. 3, Application No. U.S. 60/124,095 filedon 1999 Mar. 12, Application No. U.S. 60/138,598 filed on 1999, Jun. 11,Application No. U.S. 60/168,665 filed on 1999 Dec. 3, Application No.U.S. 60/125,360 filed on 1999 Mar. 19, Application No. U.S. 60/138,626filed on 1999, Jun. 11, Application No. U.S. 60/168,662 filed on Dec. 3,1999, Application No. U.S. 60/124,144 filed on 1999 Mar. 12, ApplicationNo. U.S. 60/138,574 filed on 1999 Jun. 11, Application No. U.S.60/168,667 filed on 1999 Dec. 3, Application No. U.S. 60/124,142 filedon 1999 Mar. 12, Application No. U.S. 60/138,597 filed on 1999 Jun. 11,Application No. U.S. 60/168,666 filed on 1999 Dec. 3, Application No.U.S. 60/125,359 filed on 1999 Mar. 19, Application No. U.S. 60/168,664filed on 1999-12403, Application No. U.S. 60/126,051 filed on 1999 Mar.23, Application No. U.S. 60/169,906 filed on 1999 Dec. 10, ApplicationNo. U.S. 60/125,362 filed on 1999 Mar. 19, Application No. U.S.60/169,980 filed on 1999 Dec. 10, Application No. U.S. 60/125,361 filedon 1999 Mar. 19, Application No. U.S. 60/169,910 filed on 1999 Dec. 10,Application No. U.S. 60/125,812 filed on 1999 Mar. 23, Application No.U.S. 60/169,936 filed on 1999 Dec. 10, Application No. U.S. 60/126,054filed on 1999 Mar. 23, Application No. U.S. 60/169,916 filed on 1999Dec. 10, Application No. U.S. 60/125,815 filed on 1999 Mar. 23,Application No. U.S. 60/169,946 filed on 1999 Dec. 10, Application No.U.S. 60/125,358 filed on 1999 Mar. 19, Application No. U.S. 60/169,616filed on 1999 Dec. 8, Application No. U.S. 60/125,364 filed on1999403-19, Application No. U.S. 60/169,623 filed on 1999 Dec. 8,Application No. U.S. 60/125,363 filed on 1999 Mar. 19, Application No.U.S. 60/169,617 filed on 1999 Dec. 8, Application No. U.S. 60/126,502filed on 1999 Mar. 26, Application No. U.S. 60/172,410 filed on 1999Dec. 17, Application No. U.S. 60/126,503 filed on 1999 Mar. 26,Application No. U.S. 60/172,409 filed on 1999 Dec. 17, Application No.U.S. 60/126,505 filed on 1999 Mar. 26, Application No. U.S. 60/172,412filed on 1999 Dec. 17, Application No. U.S. 60/126,594 filed on 1999Mar. 26, Application No. U.S. 60/172,408 filed on 1999 Dec. 17,Application No. U.S. 60/126,511 filed on 1999 Mar. 26, Application No.U.S. 60/172,413 filed on 1999 Dec. 17, Application No. U.S. 60/126,595filed on 1999 Mar. 26, Application No. U.S. 60/171,549 filed on 1999Dec. 22, Application No. U.S. 60/126,598 filed on 1999 Mar. 26,Application No. U.S. 60/171,504 filed on 1999 Dec. 22, Application No.U.S. 60/126,596 filed on 1999 Mar. 26, Application No. U.S. 60/171,552filed on 1999 Dec. 22, Application No. U.S. 60/126,600 filed on 1999Mar. 26, Application No. U.S. 60/171,550 filed on 1999 Dec. 22,Application No. U.S. 60/126,501 filed on 1999 Mar. 26, Application No.U.S. 60/171,551 filed on 1999 Dec. 22, Application No. U.S. 60/126,504filed on 1999 Mar. 26, Application No. U.S. 60/174,847 filed on 2000Jan. 7, Application No. U.S. 60/126,509 filed on 1999 Mar. 26,Application No. U.S. 60/174,853 filed on 2000 Jan. 7, Application No.U.S. 60/126,506 filed on 1994 Mar. 26, Application No. U.S. 60/174,852filed on 2000 Jan. 7, Application No. U.S. 60/242,710 filed on 2000 Oct.25, Application No. U.S. 60/126,510 filed on 1999 Mar. 26, ApplicationNo. U.S. 60/174,850 filed on 2000 Jan. 7, Application No. U.S.60/138,573 filed on 1999 Jun. 11, Application No. U.S. 60/174,851 filedon 2000 Jan. 7, Application No. U.S. 60/126,508 filed on 1999 Mar. 26,Application No. U.S. 60/174,871 filed on 2000 Jan. 7, Application No.U.S. 60/126,507 filed on 1994 Mar. 26, Application No. U.S. 60/174,872filed on 2000 Jan. 7, Application No. U.S. 60/126,597 filed on 1999 Mar.26, Application No. U.S. 60/174,877 filed on 2000 Jan. 7, ApplicationNo. U.S. 60/126,601 filed on 1999 Mar. 26, Application No. U.S.60/154,373 filed on 1999 Sep. 17, Application No. U.S. 60/176,064 filedon 2000 Jan. 14, Application No. U.S. 60/126,602 filed on 1999 Mar. 26,Application No. U.S. 60/176,063 filed on 2000 Jan. 14, Application No.U.S. 60/128,695 filed on 1999 Apr. 9, Application No. U.S. 60/176,052filed on 2000 Jan. 14, Application No. U.S. 60/128,696 filed on 1999Apr. 9, Application No. U.S. 60/176,069 filed on 2000 Jan. 14,Application No. U.S. 60/128,703 filed on 1999 Apr. 9, Application No.U.S. 60/176,068 filed on 2000 Jan. 14, Application No. U.S. 60/128,697filed on 1999 Apr. 9, Application No. U.S. 60/176,929 filed on 2000 Jan.20, Application No. U.S. 60/128,698 filed on 1999 Apr. 9, ApplicationNo. U.S. 60/176,926 filed on 2000 Jan. 20, Application No. U.S.60/128,699 filed on 1999044-09, Application No. U.S. 60/177,050 filed on2000 Jan. 20, Application No. U.S. 60/128,701 filed on 1999 Apr. 9,Application No. U.S. 60/177,166 filed on 2000 Jan. 20, Application No.U.S. 60/128,700 filed on 1999 Apr. 9, Application No. U.S. 60/176,930filed on 2000 Jan. 20, Application No. U.S. 60/128,694 filed on 1999Apr. 9, Application No. U.S. 60/176,931 filed on 2000 Jan. 20,Application No. U.S. 60/128,702 filed on 1999 Apr. 9, Application No.U.S. 60/177,049 filed on 2000 Jan. 20, Application No. U.S. 60/138,629filed on 1999 Jun. 11, Application No. U.S. 60/138,628 filed on 1999Jun. 11, Application No. U.S. 60/138,631 filed on 1999 Jun. 11,Application No. U.S. 60/138,632 filed on 1999 Jun. 11, Application No.U.S. 60/138,599 filed on 1999 Jun. 11, Application No. U.S. 60/138,572filed on 1999 Jun. 11, Application No. U.S. 60/138,625 filed on 1999Jun. 11, Application No. U.S. 60/138,633 filed on 1999 Jun. 11,Application No. U.S. 60/138,630 filed on 1999 Jun. 11, Application No.U.S. 60/138,627 filed on 1999 Jun. 11, Application No. U.S. 60/155,808filed on 1999 Sep. 27, Application No. U.S. 60/155,804 filed on 1999Sep. 27, Application No. U.S. 60/155,807 filed on 1999 Sep. 27,Application No. U.S. 60/155,805 filed on 1999 Sep. 27, Application No.U.S. 60/155,806 filed on 1999 Sep. 27, Application No. U.S. 60/201,194filed on 2000, May 2, Application No. U.S. 60/212,142 filed on 2000 Jun.16.

Indications Relating to Deposited Biological Material (PCT Rule 13bis)

A. The indications made below relate to the deposited biologicalmaterial referred to in Table 1A of the description.

B. Identification of Deposit:

-   Name of Depository: American Type Culture Collection-   Address of Depository: 10801 University Boulevard Manassas, Va.    20110-2209 United States of America    Europe

In respect of those designations in which a European Patent is sought asample of the deposited microorganism will be made available until thepublication of the mention of the grant of the European patent or untilthe date on which the application has been refused or withdrawn or isdeemed to be withdrawn, only by the issue of such a sample to an expertnominated by the person requesting the sample (Rule 28(4) EPC).

Canada

The applicant requests that, until either a Canadian patent has beenissued on the basis of an application or the application has beenrefused, or is abandoned and no longer subject to reinstatement, or iswithdrawn, the Commissioner of Patents only authorizes the furnishing ofa sample of the deposited biological material referred to in theapplication to an independent expert nominated by the Commissioner, theapplicant must, by a written statement, inform the International Bureauaccordingly before completion of technical preparations for publicationof the international application.

Norway

The applicant hereby requests that the application has been laid open topublic inspection (by the Norwegian Patent Office), or has been finallydecided upon by the Norwegian Patent Office without having been laidopen inspection, the furnishing of a sample shall only be effected to anexpert in the art. The request to this effect shall be filed by theapplicant with the Norwegian Patent Office not later than at the timewhen the application is made available to the public under Sections 22and 33(3) of the Norwegian Patents Act. If such a request has been filedby the applicant, any request made by a third party for the furnishingof a sample shall indicate the expert to be used. That expert may be anyperson entered on the list of recognized experts drawn up by theNorwegian Patent Office or any person approved by the applicant in theindividual case.

Australia

The applicant hereby gives notice that the furnishing of a sample of amicroorganism shall only be effected prior to the grant of a patent, orprior to the lapsing, refusal or withdrawal of the application, to aperson who is a skilled addressee without an interest in the invention(Regulation 3.25(3) of the Australian Patents Regulations).

Finland

The applicant hereby requests that, until the application has been laidopen to public inspection (by the National Board of Patents andRegulations), or has been finally decided upon by the National Board ofPatents and Registration without having been laid open to publicinspection, the furnishing of a sample shall only be effected to anexpert in the art.

United Kingdom

The applicant hereby requests that the furnishing of a sample of amicroorganism shall only be made available to an expert. The request tothis effect must be filed by the applicant with the International Bureaubefore the completion of the technical preparations for theinternational publication of the application.

Denmark

The applicant hereby requests that, until the application has been laidopen to public inspection (by the Danish Patent Office), or has beenfinally decided upon by the Danish Patent office without having beenlaid open to public inspection, the furnishing of a sample shall only beeffected to an expert in the art. The request to this effect shall befiled by the applicant with the Danish Patent Office not later that atthe time when the application is made available to the public underSections 22 and 33(3) of the Danish Patents Act. If such a request hasbeen filed by the applicant, any request made by a third party for thefurnishing of a sample shall indicate the expert to be used. That expertmay be any person entered on a list of recognized experts drawn up bythe Danish Patent Office or any person by the applicant in theindividual case.

Sweden

The applicant hereby requests that, until the application has been laidopen to public inspection (by the Swedish Patent Office), or has beenfinally decided upon by the Swedish Patent Office without having beenlaid open to public inspection, the furnishing of a sample shall only beeffected to an expert in the art. The request to this effect shall befiled by the applicant with the International Bureau before theexpiration of 16 months from the priority date (preferably on the FormPCT/RO/134 reproduced in annex Z of Volume I of the PCT Applicant'sGuide). If such a request has been filed by the applicant any requestmade by a third party for the furnishing of a sample shall indicate theexpert to be used. That expert may be any person entered on a list ofrecognized experts drawn up by the Swedish Patent Office or any personapproved by a applicant in the individual case.

Netherlands

The applicant hereby requests that until the date of a grant of aNetherlands patent or until the date on which the application is refusedor withdrawn or lapsed, the microorganism shall be made available asprovided in the 31F(1) of the Patent Rules only by the issue of a sampleto an expert. The request to this effect must be furnished by theapplicant with the Netherlands Industrial Property Office before thedate on which the application is made available to the public underSection 22C or Section 25 of the Patents Act of the Kingdom of theNetherlands, whichever of the two dates occurs earlier. LENGTHY TABLEThe patent application contains a lengthy table section. A copy of thetable is available in electronic form from the USPTO web site(http://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US20070032414A1)An electronic copy of the table will also be available from the USPTOupon request and payment of the fee set forth in 37 CFR 1.19(b)(3).

1-32. (canceled)
 33. An isolated nucleic acid molecule comprising afirst polynucleotide sequence at least 95% identical to a secondpolynucleotide sequence selected from the group consisting of: (a) apolynucleotide fragment of SEQ ID NO:X as referenced in Table 1A; (b) apolynucleotide encoding a full length polypeptide of SEQ ID NO:Y or afull length polypeptide encoded by the cDNA Clone ID in ATCC DepositNo:Z corresponding to SEQ ID NO:Y as referenced in Table 1A; (c) apolynucleotide encoding a polypeptide fragment of SEQ ID NO:Y or apolypeptide fragment encoded by the cDNA Clone ID in ATCC Deposit No:Zcorresponding to SEQ ID NO:Y as referenced in Table 1A; (d) apolynucleotide encoding a polypeptide fragment of SEQ ID NO:Y or apolypeptide fragment encoded by the cDNA Clone ID in ATCC Deposit No:Zcorresponding to SEQ ID NO:Y as referenced in Table 1A, wherein saidfragment has biological activity; (e) a polynucleotide encoding apolypeptide domain of SEQ ID NO:Y as referenced in Table 1B; (f) apolynucleotide encoding a polypeptide domain of SEQ ID NO:Y asreferenced in Table 2; (g) a polynucleotide encoding a predicted epitopeof SEQ ID NO:Y as referenced in Table 1B; and (h) a polynucleotidecapable of hybridizing under stringent conditions to any one of thepolynucleotides specified in (a)-(g), wherein said polynucleotide doesnot hybridize under stringent conditions to a nucleic acid moleculehaving a nucleotide sequence of only A residues or of only T residues.34. The isolated nucleic acid molecule of claim 33, wherein thepolynucleotide fragment comprises a nucleotide sequence encoding asecreted form of SEQ ID NO:Y or a secreted form of the polypeptideencoded by the cDNA Clone ID in ATCC Deposit No:Z corresponding to SEQID NO:Y, as referenced in Table 1A.
 35. The isolated nucleic acidmolecule of claim 33, wherein the polynucleotide fragment comprises anucleotide sequence encoding the sequence identified as SEQ ID NO:Y orthe polypeptide encoded by the cDNA sequence included in ATCC DepositNo:Z, which is hybridizable to SEQ ID NO:X, as referenced in Table 1A.36. The isolated nucleic acid molecule of claim 33, wherein thepolynucleotide fragment comprises the entire nucleotide sequence of SEQID NO:X or the cDNA sequence included in ATCC Deposit No:Z, which ishybridizable to SEQ ID NO:X, as referenced in Table 1A.
 37. The isolatednucleic acid molecule of claim 34, wherein the nucleotide sequencecomprises sequential nucleotide deletions from either the C-terminus orthe N-terminus.
 38. The isolated nucleic acid molecule of claim 35,wherein the nucleotide sequence comprises sequential nucleotidedeletions from either the C-terminus or the N-terminus.
 39. Arecombinant vector comprising the isolated nucleic acid molecule ofclaim
 33. 40. A method of making a recombinant host cell comprising theisolated nucleic acid molecule of claim
 33. 41. A recombinant host cellproduced by the method of claim
 40. 42. The recombinant host cell ofclaim 41 comprising vector sequences.
 43. A polypeptide comprising afirst amino acid sequence at least 95% identical to a second amino acidsequence selected from the group consisting of: (a) a full lengthpolypeptide of SEQ ID NO:Y or a full length polypeptide encoded by thecDNA Clone ID in ATCC Deposit No:Z corresponding to SEQ ID NO:Y asreferenced in Table IA; (b) a secreted form of SEQ ID NO:Y or a secretedform of the polypeptide encoded by the cDNA Clone ID in ATCC DepositNo:Z corresponding to SEQ ID NO:Y as referenced in Table 1A; (c) apolypeptide fragment of SEQ ID NO:Y or a polypeptide fragment encoded bythe cDNA Clone ID in ATCC Deposit No:Z corresponding to SEQ ID NO:Y asreferenced in Table 1A; (d) a polypeptide fragment of SEQ ID NO:Y or apolypeptide fragment encoded by the cDNA Clone ID in ATCC Deposit No:Zcorresponding to SEQ ID NO:Y as referenced in Table 1A, wherein saidfragment has biological activity; (e) a polypeptide domain of SEQ IDNO:Y as referenced in Table 1B; (f) a polypeptide domain of SEQ ID NO:Yas referenced in Table 2; and (g) a predicted epitope of SEQ ID NO:Y asreferenced in Table 1B.
 44. The polypeptide of claim 43, wherein saidpolypeptide comprises a heterologous amino acid sequence.
 45. Theisolated polypeptide of claim 43, wherein the secreted form or the fulllength protein comprises sequential amino acid deletions from either theC-terminus or the N-terminus.
 46. An isolated antibody that bindsspecifically to the isolated polypeptide of claim
 43. 47. A recombinanthost cell that expresses the isolated polypeptide of claim
 43. 48. Amethod of making an isolated polypeptide comprising: (a) culturing therecombinant host cell of claim 47 under conditions such that saidpolypeptide is expressed; and (b) recovering said polypeptide.
 49. Thepolypeptide produced by claim
 48. 50. A method for preventing, treating,or ameliorating cardiovascular disorder, comprising administering to amammalian subject a therapeutically effective amount of the polypeptideof claim
 43. 51. A method of diagnosing cardiovascular disorder in asubject comprising: (a) determining the presence or absence of amutation in the polynucleotide of claim 33; and (b) diagnosing thecardiovascular disorder based on the presence or absence of saidmutation.
 52. A method of diagnosing cardiovascular disorder in asubject comprising: (a) determining the presence or amount of expressionof the polypeptide of claim 43 in a biological sample; and (b)diagnosing the cardiovascular disorder based on the presence or amountof expression of the polypeptide.
 53. A method for identifying a bindingpartner to the polypeptide of claim 43 comprising: (a) contacting thepolypeptide of claim 43 with a binding partner; and (b) determiningwhether the binding partner effects an activity of the polypeptide. 54.The gene corresponding to the cDNA sequence of SEQ ID NO:X.
 55. A methodof identifying an activity in a biological assay, wherein the methodcomprises: (a) expressing SEQ ID NO:X in a cell; (b) isolating thesupernatant; (c) detecting an activity in a biological assay; and (d)identifying the protein in the supernatant having the activity.
 56. Theproduct produced by the method of claim 53.